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G protein-coupled receptors: novel targets for drug discovery in cancer

Key Points

  • G protein-coupled receptors (GPCRs) comprise the largest superfamily of receptors involved in transmembrane-initiated transduction pathways and are the most prominent family of validated pharmacological targets in biomedicine. Increasing evidence shows the role of GPCRs in mediating cancer cell proliferation, angiogenesis and metastasis.

  • GPCRs can crosstalk (or transactivate) with other cell surface receptors involved in cancer. For example, epidermal growth factor receptor (EGFR) signalling has a crucial role in regulating the growth, survival, migration and resistance to chemotherapies in numerous human malignancies through functional crosstalk with GPCRs. Major anticancer effects are obtained by targeting both EGFR and the endothelin A subtype receptor.

  • GPCRs and insulin/insulin-like growth factor 1 receptors cooperate in the regulation of many physiological functions as well as in the development of diverse tumours. The diabetes drug metformin prevents this cooperation; in epidemiological studies it reduced the risk of tumours in diabetic patients.

  • G protein-coupled receptor 30 (also known as G protein-coupled oestrogen receptor) mediates rapid effects induced by oestrogens and anti-oestrogens in boths normal and cancer cells. Overexpression of this receptor has been associated with negative clinical features and poor survival rates in patients with hormone-sensitive tumours.

  • The Gα12/13 subfamily of G proteins contributes to cancer development and progression, mainly through the activation of Rho family members which regulate cytoskeletal dynamics, transcriptional regulation, cell cycle progression and cell survival.

  • A GPCR named Smoothened activates the Hedgehog transduction pathway, which is implicated in the development of numerous malignancies. Accordingly, Smoothened antagonists elicit potent antitumour activity by inhibiting Hedgehog-dependent signalling.

  • Many human herpes viruses encode GPCRs which are implicated in virally induced oncogenesis. For example, the Kaposi-sarcoma-associated herpes virus encodes a GPCR that elicits transforming activity, anti-apoptotic effects, stimulation of cell growth and angiogenesis.

Abstract

G protein-coupled receptors (GPCRs) belong to a superfamily of cell surface signalling proteins that have a pivotal role in many physiological functions and in multiple diseases, including the development of cancer and cancer metastasis. Current drugs that target GPCRs — many of which have excellent therapeutic benefits — are directed towards only a few GPCR members. Therefore, huge efforts are currently underway to develop new GPCR-based drugs, particularly for cancer. We review recent findings that present unexpected opportunities to interfere with major tumorigenic signals by manipulating GPCR-mediated pathways. We also discuss current data regarding novel GPCR targets that may provide promising opportunities for drug discovery in cancer prevention and treatment.

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Figure 1: Selected transduction pathways involved in GPCR-mediated cancer signalling.
Figure 2: GPCR-induced transactivation of EGFR.
Figure 3: GPCRs and apoptotic pathways.

References

  1. Pierce, K. L., Premont, R. T. & Lefkowitz, R. J. Seven-transmembrane receptors. Nature Rev. Mol. Cell Biol. 3, 639–650 (2002).

    CAS  Article  Google Scholar 

  2. Chung, S., Funakoshi, T. & Civelli, O. Orphan GPCR research. Br. J. Pharmacol. 153, 339–346 (2008).

    Article  CAS  Google Scholar 

  3. McClanahan, T. et al. Identification of overexpression of orphan G protein-coupled receptor GPR49 in human colon and ovarian primary tumors. Cancer Biol. Ther. 5, 419–426 (2006).

    CAS  PubMed  Article  Google Scholar 

  4. Gugger, M. et al. GPR87 is an overexpressed G-protein coupled receptor in squamous cell carcinoma of the lung. Dis. Markers 24, 41–50 (2008).

    CAS  PubMed  Article  Google Scholar 

  5. Prossnitz, E. R. & Maggiolini, M. Mechanisms of estrogen signaling and gene expression via GPR30. Mol. Cell Endocrinol. 308, 32–38 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. Jin, Z., Luo, R. & Piao, X. Chapter 1 GPR56 and Its Related Diseases. Prog. Mol. Biol. Transl. Sci. 89, 1–13 (2009).

    CAS  PubMed  Article  Google Scholar 

  7. Dorsam, R. T. & Gutkind, J. S. G-protein-coupled receptors and cancer. Nature Rev. Cancer 7, 79–94. (2007).

    CAS  Article  Google Scholar 

  8. Young, D., Waitches, G., Birchmeier, C., Fasano, O. & Wigler, M. Isolation and characterization of a new cellular oncogene encoding a protein with multiple potential transmembrane domains. Cell 45, 711–719 (1986).

    CAS  PubMed  Article  Google Scholar 

  9. Santos, R. A. et al. Angiotensin-(81–7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc. Natl Acad. Sci. USA 100, 8258–8263 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. Li, S., Huang, S. & Peng, S. B. Overexpression of G protein-coupled receptors in cancer cells: involvement in tumor progression. Int. J. Oncol. 27, 1329–1339 (2005).

    CAS  PubMed  Google Scholar 

  11. Lui, V. W. et al. Mitogenic effects of gastrin-releasing peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor. Oncogene 22, 6183–6193 (2003).

    CAS  PubMed  Article  Google Scholar 

  12. Daaka, Y. G proteins in cancer: the prostate cancer paradigm. Sci. STKE 216, e2 (2004).

    Google Scholar 

  13. Ben-Baruch, A. Organ selectivity in metastasis: regulation by chemokines and their receptors. Clin. Exp. Metastasis 25, 345–356 (2008).

    CAS  PubMed  Article  Google Scholar 

  14. Greenhough, A. et al. The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis 30, 377–386 (2009).

    CAS  PubMed  Article  Google Scholar 

  15. Gerber, P. A., Hippe, A., Buhren, B. A., Müller, A. & Homey, B. Chemokines in tumor-associated angiogenesis. Biol. Chem. 390, 1213–1223 (2009).

    CAS  PubMed  Article  Google Scholar 

  16. Li, X., Lv, Y., Yuan, A. & Li, Z. Gastrin-releasing peptide links stressor to cancer progression. J. Cancer Res. Clin. Oncol. 136, 483–491 (2010).

    CAS  PubMed  Article  Google Scholar 

  17. Daub, H., Wallasch, C., Lankenau, A., Herrlich, A. & Ullrich, A. Signal characteristics of G protein-transactivated EGF receptor. EMBO J. 16, 7032–7044 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Filardo, E. J., Quinn, J. A., Bland, K. I. & Frackelton, A. R. Jr. Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol. Endocrinol. 14, 1649–1660 (2000). Thhe first description of oestrogen-induced MAPK activation through the GPCR GPER/GPR30.

    CAS  PubMed  Article  Google Scholar 

  19. Pierce, K. L., Luttrell, L. M. & Lefkowitz, R. J. New mechanisms in heptahelical receptor signaling to mitogen activated protein kinase cascades. Oncogene 20, 1532–1539 (2001).

    CAS  PubMed  Article  Google Scholar 

  20. Hart, S. et al. GPCR-induced migration of breast carcinoma cells depends on both EGFR signal transactivation and EGFR-independent pathways. Biol. Chem. 386, 845–855 (2005).

    CAS  PubMed  Article  Google Scholar 

  21. Bhola, N. E. & Grandis, J. R. Crosstalk between G-protein-coupled receptors and epidermal growth factor receptor in cancer. Front. Biosci. 13, 1857–1865 (2008).

    CAS  PubMed  Article  Google Scholar 

  22. Fischer, O. M., Hart, S. Gschwind, A. & Ullrich, A. EGFR signal transactivation in cancer cells. Biochem. Soc. Trans. 31, 1203–1208 (2003).

    CAS  PubMed  Article  Google Scholar 

  23. Blobel, C. P. ADAMs: key components in EGFR signalling and development. Nature Rev. Mol. Cell Biol. 6, 32–43 (2005).

    CAS  Article  Google Scholar 

  24. Thomas, S. M. et al. Cross-talk between G protein-coupled receptor and epidermal growth factor receptor signaling pathways contributes to growth and invasion of head and neck squamous cell carcinoma. Cancer Res. 66, 11831–11839 (2006).

    CAS  PubMed  Article  Google Scholar 

  25. Myers, T. J. et al. Mitochondrial reactive oxygen species mediate GPCR-induced TACE/ADAM17-dependent transforming growth factor-alpha shedding. Mol. Biol. Cell 20, 5236–5249 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. Gschwind, A., Hart, S., Fischer, O. M. & Ullrich, A. TACE cleavage of proamphiregulin regulates GPCR-induced proliferation and motility of cancer cells. EMBO J. 22, 2411–2421 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Balkwill, F. The significance of cancer cell expression of the chemokine receptor CXCR4. Semin. Cancer Biol. 14, 171–179 (2004).

    CAS  PubMed  Article  Google Scholar 

  28. Epstein, R. J. The CXCL12-CXCR4 chemotactic pathway as a target of adjuvant breast cancer therapies. Nature Rev. Cancer 4, 901–909 (2004).

    CAS  Article  Google Scholar 

  29. Liu, Y. et al. Expression of protease-activated receptor 1 in oral squamous cell carcinoma. Cancer Lett. 169, 173–180 (2001).

    CAS  PubMed  Article  Google Scholar 

  30. Darmoul, D., Gratio, V., Devaud, H., Lehy, T. & Laburthe, M. Aberrant expression and activation of the thrombin receptor protease-activated receptor-1 induces cell proliferation and motility in human colon cancer cells. Am. J. Pathol. 162, 1503–1513 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Tsopanoglou, N. E. & Maragoudakis, M. E. Role of thrombin in angiogenesis and tumor progression. Semin. Thromb. Hemost. 30, 63–69 (2004).

    CAS  PubMed  Article  Google Scholar 

  32. Arora, P., Ricks, T. K. & Trejo, J. Protease-activated receptor signalling, endocytic sorting and dysregulation in cancer. J. Cell Sci. 120, 921–928 (2007).

    CAS  PubMed  Article  Google Scholar 

  33. Arora, P., Cuevas, B. D., Russo, A., Johnson, G. L. & Trejo, J. Persistent transactivation of EGFR and ErbB2/HER2 by protease-activated receptor-1 promotes breast carcinoma cell invasion. Oncogene 27, 4434–4445 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Rosanò, L., Spinella, F. & Bagnato, A. The importance of endothelin axis in initiation, progression, and therapy of ovarian cancer. Am. J. Physiol. Regul. Integr Comp. Physiol. 299, R395–R404 (2010).

    PubMed  Article  CAS  Google Scholar 

  35. Rosanò, L. et al. Combined targeting of endothelin A receptor and epidermal growth factor receptor in ovarian cancer shows enhanced antitumor activity. Cancer Res. 67, 6351–6359 (2007). This study suggests the use of EGFR inhibitors in combination with ET A R antagonists as effective treatment for ovarian cancer.

    PubMed  Article  Google Scholar 

  36. Growcott, J. W. Preclinical anticancer activity of the specific endothelin A receptor antagonist ZD4054. Anticancer Drugs 20, 83–88 (2009).

    CAS  PubMed  Article  Google Scholar 

  37. Smollich, M. et al. ETAR antagonist ZD4054 exhibits additive effects with aromatase inhibitors and fulvestrant in breast cancer therapy, and improves in vivo efficacy of anastrozole. Breast Cancer Res. Treat. 123, 345–357 (2010).

    CAS  PubMed  Article  Google Scholar 

  38. Nelson, J. B. et al. Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. Cancer 113, 2478–2487 (2008).

    CAS  PubMed  Article  Google Scholar 

  39. Drake, J. M., Danke, J. R. & Henry, M. D. Bone-specific growth inhibition of prostate cancer metastasis by atrasentan. Cancer Biol. Ther. 9, 607–614 (2010). Together with references 37 and 38, this highlights the importance of ET A R antagonists as valuable anticancer drugs.

    CAS  PubMed  Article  Google Scholar 

  40. Fischgräbe, J., Götte, M., Michels, K., Kiesel, L. & Wülfing, P. Targeting endothelin A receptor enhances anti-proliferative and anti-invasive effects of the HER2 antibody trastuzumab in HER2-overexpressing breast cancer cells. Int. J. Cancer 127, 696–706 (2010).

    PubMed  Article  CAS  Google Scholar 

  41. Borrell-Pagès, M., Rojo, F., Albanell, J., Baselga, J. & Arribas, J. TACE is required for the activation of the EGFR by TGF-a in tumors. EMBO J. 22, 1114–1124 (2003).

    PubMed  PubMed Central  Article  Google Scholar 

  42. Kenny, P. A. Tackling EGFR signaling with TACE antagonists: a rational target for metalloprotease inhibitors in cancer. Expert Opin. Ther. Targets 11, 1287–1298 (2007).

    CAS  PubMed  Article  Google Scholar 

  43. Murumkar, P. R., DasGupta, S., Chandani, S. R., Giridhar, R. & Yadav, M. R. Novel TACE inhibitors in drug discovery: a review of patented compounds. Expert Opin. Ther. Pat. 20, 31–57 (2010).

    CAS  PubMed  Article  Google Scholar 

  44. Kenny, P. A. & Bissell, M. J. Targeting TACE-dependent EGFR ligand shedding in breast cancer. J. Clin. Invest. 117, 337–345 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Merchant, N. B. et al. TACE/ADAM-17: a component of the epidermal growth factor receptor axis and a promising therapeutic target in colorectal cancer. Clin. Cancer Res. 14, 1182–1191 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Ascenzi, P., Bocedi, A. & Marino, M. Structure-function relationship of estrogen receptor a and b: impact on human health. Mol. Aspects Med. 27, 299–402 (2006).

    CAS  PubMed  Article  Google Scholar 

  47. Kumar, V. & Chambon, P. The estrogen receptor binds tightly to its responsive element as a ligand-induced homodimer. Cell 55, 145–156 (1988).

    CAS  PubMed  Article  Google Scholar 

  48. Vivacqua, A. et al. The G protein-coupled receptor GPR30 mediates the proliferative effects induced by 17b-estradiol and hydroxytamoxifen in endometrial cancer cells. Mol. Endocrinol. 20, 631–646 (2006).

    CAS  PubMed  Article  Google Scholar 

  49. Vivacqua, A. et al. 17β-Estradiol, genistein, and 4-hydroxytamoxifen induce the proliferation of thyroid cancer cells through the g protein-coupled receptor GPR30. Mol. Pharmacol. 70, 1414–1423 (2006).

    CAS  PubMed  Article  Google Scholar 

  50. Albanito, L. et al. G protein-coupled receptor 30 (GPR30) mediates gene expression changes and growth response to 17b-estradiol and selective GPR30 ligand G-1 in ovarian cancer cells. Cancer Res. 67, 1859–1866 (2007).

    CAS  PubMed  Article  Google Scholar 

  51. Maggiolini, M. & Picard, D. The unfolding stories of GPR30, a new membrane-bound estrogen receptor. J. Endocrinol. 204, 105–114 (2010).

    CAS  PubMed  Article  Google Scholar 

  52. Chan, Q. K. et al. Activation of GPR30 inhibits the growth of prostate cancer cells through sustained activation of Erk1/2, c-jun/c-fos-dependent upregulation of p21, and induction of G2 cell-cycle arrest. Cell Death Differ. 17, 1511–1523 (2010).

    CAS  PubMed  Article  Google Scholar 

  53. Bologa, C. G. et al. Virtual and biomolecular screening converge on a selective agonist for GPR30. Nature Chem. Biol. 2, 207–212 (2006).

    CAS  Article  Google Scholar 

  54. Vivacqua, A. et al. G protein-coupled receptor 30 expression is up-regulated by EGF and TGF a in estrogen receptor a-positive cancer cells. Mol. Endocrinol. 23, 1815–1826 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. Pandey, D. P. et al. Estrogenic GPR30 signalling induces proliferation and migration of breast cancer cells through CTGF. EMBO J. 28, 523–532 (2009). Provides a systematic characterization of the genomic responses to oestrogenic GPR30 signalling in breast cancer cells.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  56. Albanito, L. et al. Epidermal growth factor induces G protein-coupled receptor 30 expression in estrogen receptor-negative breast cancer cells. Endocrinology 149, 3799–3808 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Madeo, A. & Maggiolini, M. Nuclear alternate estrogen receptor GPR30 mediates 17b-estradiol-induced gene expression and migration in breast cancer-associated fibroblasts. Cancer Res. 70, 6036–6046 (2010).

    CAS  PubMed  Article  Google Scholar 

  58. Kalluri, R. & Zeisberg, M. Fibroblasts in cancer. Nature Rev. Cancer 6, 392–401 (2006).

    CAS  Article  Google Scholar 

  59. Albini, A. & Sporn, M. B. The tumour microenvironment as a target for chemoprevention. Nature Rev. Cancer 7, 139–147 (2007).

    CAS  Article  Google Scholar 

  60. Finak, G. et al. Stromal gene expression predicts clinical outcome in breast cancer. Nature Med. 14, 518–527 (2008).

    CAS  PubMed  Article  Google Scholar 

  61. Filardo, E. J. et al. Distribution of GPR30, a seven membrane-spanning estrogen receptor, in primary breast cancer and its association with clinicopathologic determinants of tumor progression. Clin. Cancer Res. 12, 6359–6366 (2006).

    CAS  PubMed  Article  Google Scholar 

  62. Smith, H. O. et al. GPR30: a novel indicator of poor survival for endometrial carcinoma. Am. J. Obstet. Gynecol. 196, 386.e1–386.e11 (2007).

    Google Scholar 

  63. Smith, H. O. et al. GPR30 predicts poor survival for ovarian cancer. Gynecol. Oncol. 114, 465–471 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Rozengurt, E., Sinnett-Smith, J. & Kisfalvi, K. Crosstalk between insulin/insulin-like growth factor-1 receptors and G protein-coupled receptor signaling systems: a novel target for the antidiabetic drug metformin in pancreatic cancer. Clin. Cancer Res. 16, 2505–2511 (2010). Shows that metformin disrupts crosstalk between insulin/IGF I receptor and GPCR signalling in pancreatic cancer cells.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. Kisfalvi, K., Rey, O., Young, S. H., Sinnett-Smith, J. & 2+ Rozengurt, E. Insulin potentiates Ca signaling and phosphatidylinositol 4,5-bisphosphate hydrolysis induced by Gq protein-coupled receptor agonists through an mTOR-dependent pathway. Endocrinology 148, 3246–3257 (2007).

    CAS  PubMed  Article  Google Scholar 

  66. Taniguchi, C. M., Emanuelli, B. & Kahn, C. R. Critical nodes in signalling pathways: insights into insulin action. Nature Rev. Mol. Cell Biol. 7, 85–96 (2006).

    CAS  Article  Google Scholar 

  67. Buzzai, M. et al. Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res. 67, 6745–6752 (2007).

    CAS  PubMed  Article  Google Scholar 

  68. Dowling, R. J., Zakikhani, M., Fantus, I. G., Pollak, M. & Sonenberg, N. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res. 67, 10804–10812 (2007).

    CAS  PubMed  Article  Google Scholar 

  69. Kisfalvi, K., Eibl, G., Sinnett-Smith, J. & Rozengurt, E. Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Res. 69, 6539–6545 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. Vazquez-Martin, A. et al. Metformin regulates breast cancer stem cell ontogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status. Cell Cycle 9, 3807–3814 (2010).

    CAS  PubMed  Article  Google Scholar 

  71. Li, D., Yeung, S. C., Hassan, M. M., Konopleva, M. & Abbruzzese, J. L. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology 137, 482–488 (2009).

    PubMed  Article  Google Scholar 

  72. van der Veeken, J. et al. Crosstalk between epidermal growth factor receptor- and insulin-like growth factor-1 receptor signaling: implications for cancer therapy. Curr. Cancer Drug Targets 9, 748–760 (2009).

    CAS  PubMed  Article  Google Scholar 

  73. Chan, A. M. et al. Expression cDNA cloning of a transforming gene encoding the wild-type Ga12 gene product. Mol. Cell Biol. 13, 762–768 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Radhika, V. & Dhanasekaran, N. Transforming G proteins. Oncogene 20, 1607–1614 (2001).

    CAS  PubMed  Article  Google Scholar 

  75. Bian, D. et al. The G12/13-RhoA signaling pathway contributes to efficient lysophosphatidic acid-stimulated cell migration. Oncogene 25, 2234–2244 (2006).

    CAS  PubMed  Article  Google Scholar 

  76. Xu, X. & Prestwich, G. D. Inhibition of tumor growth and angiogenesis by a lysophosphatidic acid antagonist in an engineered three-dimensional lung cancer xenograft model. Cancer 116, 1739–1750 (2010).

    CAS  PubMed  Article  Google Scholar 

  77. Shan, D. et al. The G protein Ga13 is required for growth factor-induced cell migration. Dev. Cell 10, 707–718 (2006).

    CAS  PubMed  Article  Google Scholar 

  78. Even-Ram, S. et al. Thrombin receptor overexpression in malignant and physiological invasion processes. Nature Med. 4, 909–914 (1998).

    CAS  PubMed  Article  Google Scholar 

  79. Meigs, T. E., Fedor-Chaiken, M., Kaplan, D. D., Brackenbury, R. & Casey, P. J. Ga12 and Ga13 negatively regulate the adhesive functions of cadherin. J. Biol. Chem. 277, 24594–24600 (2002).

    CAS  PubMed  Article  Google Scholar 

  80. Grise, F., Bidaud, A. & Moreau, V. Rho GTPases in hepatocellular carcinoma. Biochim. Biophys. Acta 1795, 137–151 (2009).

    CAS  PubMed  Google Scholar 

  81. Juneja, J. & Casey, P. J. Role of G12 proteins in oncogenesis and metastasis. Br. J. Pharmacol. 158, 32–40 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. Heasman, S. J. & Ridley, A. J. Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nature Rev. Mol. Cell Biol. 9, 690–701 (2008).

    CAS  Article  Google Scholar 

  83. Vega, F. M. & Ridley, A. J. Rho GTPases in cancer cell biology. FEBS Lett. 582, 2093–2101 (2008).

    CAS  PubMed  Article  Google Scholar 

  84. Martin, C. B. et al. The thrombin receptor, PAR-1, causes transformation by activation of Rho-mediated signaling pathways. Oncogene 20, 1953–1963 (2001). Shows that PAR1 dependent transformation is mediated by RHOA activation.

    CAS  PubMed  Article  Google Scholar 

  85. Radeff-Huang, J., Seasholtz, T. M., Matteo, R. G. & Brown, J. H. G protein mediated signaling pathways in lysophospholipid induced cell proliferation and survival. J. Cell Biochem. 92, 949–966 (2004).

    CAS  PubMed  Article  Google Scholar 

  86. Malchinkhuu, E. et al. Role of p38 mitogen-activated kinase and c-Jun terminal kinase in migration response to lysophosphatidic acid and sphingosine-1-phosphate in glioma cells. Oncogene 24, 6676–6688 (2005).

    CAS  PubMed  Article  Google Scholar 

  87. Young, N. & Van Brocklyn, J. R. Roles of sphingosine-1-phosphate (S1P) receptors in malignant behavior of glioma cells. Differential effects of S1P2 on cell migration and invasiveness. Exp. Cell Res. 313, 1615–1627 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. Malchinkhuu, E. et al. S1P(2) receptors mediate inhibition of glioma cell migration through Rho signaling pathways independent of PTEN. Biochem. Biophys. Res. Commun. 366, 963–968 (2008).

    CAS  PubMed  Article  Google Scholar 

  89. Balkwill, F. Cancer and the chemokine network. Nature Rev. Cancer 4, 540–550 (2004).

    CAS  Article  Google Scholar 

  90. Müller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 410, 50–56 (2001).

    PubMed  Article  Google Scholar 

  91. Staller, P. et al. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 425, 307–311 (2003).

    CAS  PubMed  Article  Google Scholar 

  92. Bartolomé, R. A. et al. Stromal cell-derived factor-1a promotes melanoma cell invasion across basement membranes involving stimulation of membrane-type 1 matrix metalloproteinase and Rho GTPase activities. Cancer Res. 64, 2534–2543 (2004).

    PubMed  Article  Google Scholar 

  93. Bartolomé, R. A. et al. Activated G.a13 impairs cell invasiveness through p190RhoGAP-mediated inhibition of RhoA activity. Cancer Res. 68, 8221–8230 (2008).

    PubMed  Article  CAS  Google Scholar 

  94. García-López, M. T., Gutiérrez-Rodríguez, M. & Herranz, R. Thrombin-activated receptors: promising targets for cancer therapy? Curr. Med. Chem. 17, 109–128 (2010).

    PubMed  Article  Google Scholar 

  95. Hu, L., Roth, J. M., Brooks, P., Ibrahim, S. & Karpatkin, S. Twist is required for thrombin-induced tumor angiogenesis and growth. Cancer Res. 68, 4296–4302 (2008).

    CAS  PubMed  Article  Google Scholar 

  96. Hu, L., Roth, J. M., Brooks, P., Luty, J. & Karpatkin, S. Thrombin up-regulates cathepsin D which enhances angiogenesis, growth, and metastasis. Cancer Res. 68, 4666–4673 (2008).

    CAS  PubMed  Article  Google Scholar 

  97. Contos, J. J., Ishii, I. & Chun, J. Lysophosphatidic acid receptors. Mol. Pharmacol. 58, 1188–1196 (2000).

    CAS  PubMed  Article  Google Scholar 

  98. Noguchi, K., Ishii, S. & Shimizu, T. Identification of p2y9/GPR23 as a novel G protein-coupled receptor for lysophosphatidic acid, structurally distant from the Edg family. J. Biol. Chem. 278, 25600–25606 (2003).

    CAS  PubMed  Article  Google Scholar 

  99. Lee, C. W., Rivera, R., Gardell, S., Dubin, A. E & Chun, J. GPR92 as a new G12/13- and Gq-coupled lysophosphatidic acid receptor that increases cAMP, LPA5. J. Biol. Chem. 281, 23589–23597 (2006).

    CAS  PubMed  Article  Google Scholar 

  100. Tabata, K., Baba, K., Shiraishi, A., Ito, M. & Fujita, N. The orphan GPCR GPR87 was deorphanized and shown to be a lysophosphatidic acid receptor. Biochem. Biophys. Res. Commun. 363, 861–866 (2007).

    CAS  Article  PubMed  Google Scholar 

  101. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    CAS  PubMed  Article  Google Scholar 

  102. Oyesanya, R. A. et al. Differential requirement of the epidermal growth factor receptor for G protein-mediated activation of transcription factors by lysophosphatidic acid. Mol. Cancer 9, 8 (2010). Highlights the mechanisms by which EGFR triggers G protein-mediated signalling by LPA.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  103. Mills, G. B. & Moolenaar, W. H. The emerging role of lysophosphatidic acid in cancer. Nature Rev. Cancer 3, 582–591 (2003).

    CAS  Article  Google Scholar 

  104. Yang, M. et al. G protein-coupled lysophosphatidic acid receptors stimulate proliferation of colon cancer cells through the b-catenin pathway. Proc. Natl Acad. Sci. USA 102, 6027–6032 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  105. Chen, M., Towers, L. N. & O'Connor, K. L. LPA2 (EDG4) mediates Rho-dependent chemotaxis with lower efficacy than LPA1 (EDG2) in breast carcinoma cells. Am. J. Physiol. Cell Physiol. 292, C1927–C1933 (2007).

    CAS  PubMed  Article  Google Scholar 

  106. Jeong, K. J. et al. Lysophosphatidic acid receptor 2 and Gi/Src pathway mediate cell motility through cyclooxygenase 2 expression in CAOV-3 ovarian cancer cells. Exp. Mol. Med. 40, 607–616 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. Prestwich, G. D. et al. Phosphatase-resistant analogues of lysophosphatidic acid: agonists promote healing, antagonists and autotaxin inhibitors treat cancer. Biochim. Biophys. Acta 1781, 588–594 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. Jiang, G. et al. Alpha-substituted phosphonate analogues of lysophosphatidic acid (LPA) selectively inhibit production and action of LPA. ChemMedChem 2, 679–690 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. Xu, Y. et al. Structure-activity relationships of fluorinated lysophosphatidic acid analogues. J. Med. Chem. 48, 3319–3327 (2005).

    CAS  PubMed  Article  Google Scholar 

  110. Aoki, J. et al. Serum lysophosphatidic acid is produced through diverse phospholipase pathways. J. Biol. Chem. 277, 48737–48744 (2002).

    CAS  PubMed  Article  Google Scholar 

  111. Nam, S. W. et al. Autotaxin (ATX), a potent tumor motogen, augments invasive and metastatic potential of ras-transformed cells. Oncogene 19, 241–247 (2000).

    CAS  PubMed  Article  Google Scholar 

  112. van Meeteren, L. A. et al. Inhibition of autotaxin by lysophosphatidic acid and sphingosine 1-phosphate. J. Biol. Chem. 280, 21155–21161 (2005).

    CAS  PubMed  Article  Google Scholar 

  113. Umezu-Goto, M. et al. Lysophosphatidic acid production and action: validated targets in cancer? J. Cell Biochem. 92, 1115–1140 (2004).

    CAS  PubMed  Article  Google Scholar 

  114. Baker, D. L. et al. Carba analogs of cyclic phosphatidic acid are selective inhibitors of autotaxin and cancer cell invasion and metastasis. J. Biol. Chem. 281, 22786–22793 (2006).

    CAS  PubMed  Article  Google Scholar 

  115. Saunders, L. P. et al. Identification of small-molecule inhibitors of autotaxin that inhibit melanoma cell migration and invasion. Mol. Cancer Ther. 7, 3352–3362 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  116. Zhang, H. et al. Dual activity lysophosphatidic acid receptor pan-antagonist/autotaxin inhibitor reduces breast cancer cell migration in vitro and causes tumor regression in vivo. Cancer Res. 69, 5441–5449 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. Ingham, P. W. & McMahon, A. P. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 15, 3059–3087 (2001).

    CAS  PubMed  Article  Google Scholar 

  118. Jiang, J. & Hui, C. C. Hedgehog signaling in development and cancer. Dev. Cell 15, 801–812 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. Ayers, K. L. & Thérond, P. P. Evaluating Smoothened as a G-protein-coupled receptor for Hedgehog signalling. Trends Cell Biol. 20, 287–298 (2010).

    CAS  PubMed  Article  Google Scholar 

  120. Kasper, M., Regl, G., Frischauf, A. M. & Aberger, F. GLI transcription factors: mediators of oncogenic Hedgehog signalling. Eur. J. Cancer 42, 437–445 (2006).

    CAS  PubMed  Article  Google Scholar 

  121. Varjosalo, M. & Taipale, J. Hedgehog: functions and mechanisms. Genes Dev. 22, 2454–2472 (2008).

    CAS  PubMed  Article  Google Scholar 

  122. Katoh, Y. & Katoh, M. Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation. Curr. Mol. Med. 9, 873–886 (2009).

    CAS  PubMed  Article  Google Scholar 

  123. Kawahara, T. et al. Cyclopamine and quercetin suppress the growth of leukemia and lymphoma cells. Anticancer Res. 29, 4629–4632 (2009).

    CAS  PubMed  Google Scholar 

  124. Mimeault, M., Johansson, S. L., Henichart, J. P., Depreux, P. & Batra, S. K. Cytotoxic effects induced by docetaxel, gefitinib, and cyclopamine on side population and nonside population cell fractions from human invasive prostate cancer cells. Mol. Cancer Ther. 9, 617–630 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. Yang, Y. et al. Expression and regulation of hedgehog signaling pathway in pancreatic cancer. Langenbecks Arch. Surg. 395, 515–525 (2010).

    PubMed  Article  Google Scholar 

  126. Yoo, Y. A., Kang, M. H., Kim, J. S. & Oh, S. C. Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-b-mediated activation of the ALK5-Smad 3 pathway. Carcinogenesis 29, 480–490 (2008).

    CAS  PubMed  Article  Google Scholar 

  127. Cheng, W. T. et al. Role of Hedgehog signaling pathway in proliferation and invasiveness of hepatocellular carcinoma cells. Int. J. Oncol. 34, 829–836 (2009).

    CAS  PubMed  Google Scholar 

  128. Siegelin, M. D., Siegelin, Y., Habel, A., Rami, A. & Gaiser, T. KAAD-cyclopamine augmented TRAIL-mediated apoptosis in malignant glioma cells by modulating the intrinsic and extrinsic apoptotic pathway. Neurobiol. Dis. 34, 259–266 (2009).

    CAS  PubMed  Article  Google Scholar 

  129. Tremblay, M. R. et al. Discovery of a potent and orally active Hedgehog pathway antagonist (IPI-926). J. Med. Chem. 52, 4400–4418 (2009). Demonstrates that the Hedgehog inhibitor IPI-926 induces tumour regression in experimental animal models.

    CAS  PubMed  Article  Google Scholar 

  130. Feldmann, G. et al. An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer. Mol. Cancer Ther. 7, 2725–2735 (2008).

    CAS  Article  Google Scholar 

  131. Campos, S. M. & Ghosh, S. A current review of targeted therapeutics for ovarian cancer. J. Oncol. 2010, 149362 (2010).

  132. Olive, K. P. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 324, 1457–1461 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. Remsberg, J. R., Lou, H., Tarasov, S. G., Dean, M. & Tarasova, N. I. Structural analogues of smoothened intracellular loops as potent inhibitors of Hedgehog pathway and cancer cell growth. J. Med. Chem. 50, 4534–4538 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. Miller-Moslin, K. et al. 1-amino-4-benzylphthalazines as orally bioavailable smoothened antagonists with antitumor activity. J. Med. Chem. 52, 3954–3968 (2009).

    CAS  PubMed  Article  Google Scholar 

  135. Teglund, S. & Toftgård, R. Hedgehog beyond medulloblastoma and basal cell carcinoma. Biochim. Biophys. Acta 1805, 181–208 (2010).

    CAS  PubMed  Google Scholar 

  136. Rudin, C. M. et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N. Engl. J. Med. 361, 1173–1178 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. Yauch, R. L. et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science 326, 572–574 (2009). Provides evidence that acquired Smoothened mutation can serve as a mechanism of resistance to Hedgehog pathway inhibitor in medulloblastoma.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. Lauth, M., Bergström, A., Shimokawa, T. & Toftgård, R. Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc. Natl Acad. Sci. USA 104, 8455–8460 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  139. Lustig, B. & Behrens, J. The Wnt signaling pathway and its role in tumor development. J. Cancer Res. Clin. Oncol. 129, 199–221 (2003).

    CAS  PubMed  Article  Google Scholar 

  140. Yang, S. H. et al. Pathological responses to oncogenic Hedgehog signaling in skin are dependent on canonical Wnt/b3-catenin signaling. Nature Genet. 40, 1130–1135 (2008).

    CAS  PubMed  Article  Google Scholar 

  141. He, X., Semenov, M., Tamai, K. & Zeng, X. LDL receptor-related proteins 5 and 6 in Wnt/b-catenin signaling: arrows point the way. Development 131, 1663–1677 (2004).

    CAS  PubMed  Article  Google Scholar 

  142. Clevers, H. Wnt/b-catenin signaling in development and disease. Cell 127, 469–480 (2006).

    CAS  PubMed  Article  Google Scholar 

  143. Rubinfeld, B. et al. Binding of GSK3b to the APC-beta-catenin complex and regulation of complex assembly. Science 272, 1023–1026 (1996).

    CAS  PubMed  Article  Google Scholar 

  144. Orford, K., Crockett, C., Jensen, J. P., Weissman, A. M. & Byers, S. W. Serine phosphorylation-regulated ubiquitination and degradation of b-catenin. J. Biol. Chem. 272, 24735–24738 (1997).

    CAS  PubMed  Article  Google Scholar 

  145. Lai, S. L., Chien, A. J. & Moon, R. T. Wnt/Fz signaling and the cytoskeleton: potential roles in tumorigenesis. Cell Res. 19, 532–545 (2009).

    CAS  PubMed  Article  Google Scholar 

  146. Revet, I. et al. MSX1 induces the Wnt pathway antagonist genes DKK1, DKK2, DKK3, and SFRP1 in neuroblastoma cells, but does not block Wnt3 and Wnt5A signalling to DVL3. Cancer Lett. 289, 195–207 (2010).

    CAS  PubMed  Article  Google Scholar 

  147. Cadigan, K. M. & Liu, Y. I. Wnt signaling: complexity at the surface. J. Cell Sci. 119, 395–402 (2006).

    CAS  PubMed  Article  Google Scholar 

  148. Vincan, E. et al. Frizzled-7 dictates three-dimensional organization of colorectal cancer cell carcinoids. Oncogene 26, 2340–2352 (2007).

    CAS  PubMed  Article  Google Scholar 

  149. Prévost, G. P. et al. Anticancer activity of BIM-46174, a new inhibitor of the heterotrimeric Ga/Gbg protein complex. Cancer Res. 66, 9227–9234 (2006).

    PubMed  Article  CAS  Google Scholar 

  150. Fukukawa, C. et al. Activation of the non-canonical Dvl-Rac1-JNK pathway by Frizzled homologue 10 in human synovial sarcoma. Oncogene 28, 1110–1120 (2009).

    CAS  PubMed  Article  Google Scholar 

  151. Ueno, K. et al. Down-regulation of frizzled-7 expression decreases survival, invasion and metastatic capabilities of colon cancer cells. Br. J. Cancer 101, 1374–1381 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. Liu, C. C., Prior, J., Piwnica-Worms, D. & Bu, G. LRP6 overexpression defines a class of breast cancer subtype and is a target for therapy. Proc. Natl Acad. Sci. USA 107, 5136–5141 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  153. Brown, A. M. Wnt signaling in breast cancer: have we come full circle? Breast Cancer Res. 3, 351–355 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. Barker, N. & Clevers, H. Mining the Wnt pathway for cancer therapeutics. Nature Rev. Drug Discov. 5, 997–1014 (2006).

    CAS  Article  Google Scholar 

  155. Shan, B. E., Wang, M. X. & Li, R. Q. Quercetin inhibit human SW480 colon cancer growth in association with inhibition of cyclin D1 and survivin expression through Wnt/b-catenin signaling pathway. Cancer Invest. 27, 604–612 (2009).

    CAS  PubMed  Article  Google Scholar 

  156. Lu, D. et al. Ethacrynic acid exhibits selective toxicity to chronic lymphocytic leukemia cells by inhibition of the Wnt/b-catenin pathway. PLoS One 4, e8294 (2009).

    Article  CAS  Google Scholar 

  157. Choi, H. et al. Murrayafoline A attenuates the Wnt/b-catenin pathway by promoting the degradation of intracellular b-catenin proteins. Biochem. Biophys. Res. Commun. 391, 915–920 (2010).

    CAS  PubMed  Article  Google Scholar 

  158. Wang, P. S. et al. Thiazolidinediones downregulate Wnt/b-catenin signaling via multiple mechanisms in breast cancer cells. J. Surg. Res. 153, 210–216 (2009).

    CAS  PubMed  Article  Google Scholar 

  159. Garber, K. Drugging the Wnt pathway: problems and progress. J. Natl Cancer Inst. 101, 548–550 (2009).

    PubMed  Article  Google Scholar 

  160. Fang, X. et al. Lysophosphatidic acid prevents apoptosis in fibroblasts via G; protein-mediated activation of mitogen-activated protein kinase. Biochem. J. 352, 135–143 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. Marinissen, M. J. & Gutkind, J. S. G. protein-coupled receptors and signaling networks: emerging paradigms. Trends Pharmacol. Sci. 22, 368–376 (2001).

    CAS  PubMed  Article  Google Scholar 

  162. Zhou, Y., Larsen, P. H., Hao, C. & Yong, V. W. CXCR4 is a major chemokine receptor on glioma cells and mediates their survival. J. Biol. Chem. 277, 49481–49487 (2002).

    CAS  PubMed  Article  Google Scholar 

  163. Baudhuin, L. M., Cristina, K. L., Lu, J. & Xu, Y. Akt activation induced by lysophosphatidic acid and sphingosine-1-phosphate requires both mitogen-activated protein kinase kinase and p38 mitogen-activated protein kinase and is cell-line specific. Mol. Pharmacol. 62, 660–671 (2002).

    CAS  PubMed  Article  Google Scholar 

  164. Van Brocklyn, J. R. et al. Dual actions of sphingosine-1-phosphate: extracellular through the Gi-coupled receptor Edg-1 and intracellular to regulate proliferation and survival. J. Cell Biol. 142, 229–240 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  165. Lai, J. M., Hsieh, C. L. & Chang, Z. F. Caspase activation during phorbol ester-induced apoptosis requires ROCK-dependent myosin-mediated contraction. J. Cell Sci. 116, 3491–3501 (2003).

    CAS  PubMed  Article  Google Scholar 

  166. Voisin, T., El Firar, A., Rouyer-Fessard, C., Gratio, V. & Laburthe, M. A hallmark of immunoreceptor, the tyrosine-based inhibitory motif ITIM, is present in the G protein-coupled receptor O1R for orexins and drives apoptosis: a novel mechanism. FASEB J. 22, 1993–2002 (2008).

    CAS  PubMed  Article  Google Scholar 

  167. Wagener, B. M., Marjon, N. A., Revankar, C. M. & Prossnitz, E. R. Adaptor protein-2 interaction with arrestin regulates GPCR recycling and apoptosis. Traffic 10, 1286–1300 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  168. Sengupta, S. & Harris, C. C. p53: traffic cop at the crossroads of DNA repair and recombination. Nature Rev. Mol. Cell Biol. 6, 44–55 (2005).

    CAS  Article  Google Scholar 

  169. Haupt, S. & Haupt. Y. Importance of p53 for cancer onset and therapy. Anticancer Drugs 17, 725–732 (2006).

    CAS  PubMed  Article  Google Scholar 

  170. Zhang, Y., Qian, Y., Lu, W. & Chen, X. The G protein-coupled receptor 87 is necessary for p53-dependent cell survival in response to genotoxic stress. Cancer Res. 69, 6049–6056 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  171. Murph, M. M., Hurst-Kennedy, J., Newton, V., Brindley, D. N. & Radhakrishna, H. Lysophosphatidic acid decreases the nuclear localization and cellular abundance of the p53 tumor suppressor in A549 lung carcinoma cells. Mol. Cancer Res. 5, 1201–1211 (2007).

    CAS  PubMed  Article  Google Scholar 

  172. Chen, X. et al. G-protein-coupled receptor kinase 5 phosphorylates p53 and inhibits DNA damage-induced apoptosis. J. Biol. Chem. 285, 12823–12830 (2010). Identifies GRK5 as a negative regulator of p53-mediated signalling.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  173. Moskovits, N., Kalinkovich, A., Bar, J., Lapidot, T. & Oren, M. p53 Attenuates cancer cell migration and invasion through repression of SDF-1/CXCL12 expression in stromal fibroblasts. Cancer Res. 66, 10671–10676 (2006).

    CAS  PubMed  Article  Google Scholar 

  174. Fraser, C. C. G protein-coupled receptor connectivity to NF-kB in inflammation and cancer. Int. Rev. Immunol. 27, 320–350 (2008).

    CAS  PubMed  Article  Google Scholar 

  175. Baud, V. & Karin, M. Is NF-kB a good target for cancer therapy? Hopes and pitfalls. Nature Rev. Drug Discov. 8, 33–40 (2009).

    CAS  Article  Google Scholar 

  176. Wang, C. Y., Cusack, J. C. J., Liu, R. & Baldwin, A. S. Jr. Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kB. Nature Med. 5, 412–417 (1999).

    PubMed  Article  CAS  Google Scholar 

  177. Lee, C. H., Jeon, Y. T., Kim, S. H. & Song, Y. S. NF-kB as a potential molecular target for cancer therapy. Biofactors 29, 19–35 (2007).

    CAS  PubMed  Article  Google Scholar 

  178. Wang, D. et al. Bcl10 plays a critical role in NF-kB activation induced by G protein-coupled receptors. Proc. Natl Acad. Sci. USA 104, 145–150 (2007).

    CAS  PubMed  Article  Google Scholar 

  179. Grabiner, B. C. et al. CARMA3 deficiency abrogates G protein-coupled receptor-induced NF-kB activation. Genes Dev. 21, 984–996 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  180. Sun, J. & Lin, X. b-arrestin 2 is required for lysophosphatidic acid-induced NF-kB activation. Proc. Natl Acad. Sci. USA 105, 17085–17090 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  181. Kinoshita, J. et al. Local angiotensin II-generation in human gastric cancer: correlation with tumor progression through the activation of ERK1/2, NF-kB and survivin. Int. J. Oncol. 34, 1573–1582 (2009).

    CAS  PubMed  Article  Google Scholar 

  182. Yang, W. H. et al. Bradykinin enhances cell migration in human chondrosarcoma cells through BK receptor signaling pathways. J. Cell Biochem. 109, 82–92 (2010).

    CAS  PubMed  Google Scholar 

  183. Bar-Yehuda, S. et al. CF101, an agonist to the A3 adenosine receptor, enhances the chemotherapeutic effect of 5-fluorouracil in a colon carcinoma murine model. Neoplasia 7, 85–90 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  184. Fishman, P. et al. An agonist to the A3 adenosine receptor inhibits colon carcinoma growth in mice via modulation of GSK-3 beta and NF-k, B. Oncogene 23, 2465–2471 (2004).

    CAS  PubMed  Article  Google Scholar 

  185. Vischer, H. F., Hulshof, J. W., de Esch, I. J., Smit, M. J. & Leurs, R. Virus-encoded G-protein-coupled receptors: constitutively active (dys)regulators of cell function and their potential as drug target. Ernst Schering Found. Symp. Proc. 2, 187–209 (2006).

    Google Scholar 

  186. Chang, Y. et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266, 1865–1869 (1994).

    CAS  PubMed  Article  Google Scholar 

  187. Kirshner, J. R., Staskus, K., Haase, A., Lagunoff, M. & Ganem, D. Expression of the open reading frame 74 (G-protein-coupled receptor) gene of Kaposi's sarcoma (KS)-associated herpesvirus: implications for KS pathogenesis. J. Virol. 73, 6006–6014 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  188. Montaner, S. et al. The Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor as a therapeutic target for the treatment of Kaposi's sarcoma. Cancer Res. 66, 168–174 (2006).

    CAS  PubMed  Article  Google Scholar 

  189. Ho, H. H., Du, D. & Gershengorn, M. C. The N terminus of Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor is necessary for high affinity chemokine binding but not for constitutive activity. J. Biol. Chem. 274, 31327–31332 (1999).

    CAS  PubMed  Article  Google Scholar 

  190. Holst, P. J. et al. Tumorigenesis induced by the HHV8-encoded chemokine receptor requires ligand modulation of high constitutive activity. J. Clin. Invest. 108, 1789–1796 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  191. Feng, H., Dong, X., Negaard, A. & Feng, P. Kaposi's sarcoma-associated herpesvirus K7 induces viral G protein-coupled receptor degradation and reduces its tumorigenicity. PLoS Pathog. 4, 1–16 (2008).

    Article  CAS  Google Scholar 

  192. Bais, C. et al. G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature. 391, 86–89 (1998). Demonstrates that the KSHV GPCR-mediated signalling induces transformation and angiogenesis.

    CAS  PubMed  Article  Google Scholar 

  193. Yang, T. Y. et al. Transgenic expression of the chemokine receptor encoded by human herpesvirus 8 induces an angioproliferative disease resembling Kaposi's sarcoma. J. Exp. Med. 191, 445–454 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  194. Montaner, S. et al. Endothelial infection with KSHV genes in vivo reveals that vGPCR initiates Kaposi's sarcomagenesis and can promote the tumorigenic potential of viral latent genes. Cancer Cell 3, 23–36 (2003).

    CAS  PubMed  Article  Google Scholar 

  195. Gonzalez-Pardo, V. et al. 1a, 25-dihydroxyvitamin D3 and its TX527 analog inhibit the growth of endothelial cells transformed by Kaposi sarcoma-associated herpes virus G protein-coupled receptor in vitro and in vivo. Endocrinology 151, 23–31 (2010).

    CAS  PubMed  Article  Google Scholar 

  196. Sodhi, A. et al. The Kaposi's sarcoma-associated herpes virus G protein-coupled receptor up-regulates vascular endothelial growth factor expression and secretion through mitogen-activated protein kinase and p38 pathways acting on hypoxia-inducible factor 1a. Cancer Res. 60, 4873–4880 (2000).

    CAS  PubMed  Google Scholar 

  197. Damania, B. Oncogenic g-herpesviruses: comparison of viral proteins involved in tumorigenesis. Nature Rev. Microbiol. 2, 656–668 (2004).

    CAS  Article  Google Scholar 

  198. Paulsen, S. J., Rosenkilde, M. M., Eugen-Olsen, J. & Kledal, T. N. Epstein-Barr virus-encoded BILF1 is a constitutively active G protein-coupled receptor. J. Virol. 79, 536–546 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  199. Beisser, P. S. et al. The Epstein-Barr virus BILF1 gene encodes a G protein-coupled receptor that inhibits phosphorylation of RNA-dependent protein kinase. J. Virol. 79, 441–449 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  200. Zuo, J. et al. The Epstein-Barr virus G-protein-coupled receptor contributes to immune evasion by targeting MHC class I molecules for degradation. PLoS Pathog. 5, 1–16 (2009).

    Article  CAS  Google Scholar 

  201. Rowe, M. & Zuo, J. Immune responses to Epstein-Barr virus: molecular interactions in the virus evasion of CD8+ T cell immunity. Microbes Infect. 12, 173–181 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  202. Sabatier, J. et al. Detection of human cytomegalovirus genome and gene products in central nervous system tumours. Br. J. Cancer 92, 747–750 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  203. Harkins, L. et al. Specific localisation of human cytomegalovirus nucleic acids and proteins in human colorectal cancer. Lancet. 360, 1557–1563 (2002).

    CAS  PubMed  Article  Google Scholar 

  204. Söderberg-Nauclér, C. HCMV microinfections in inflammatory diseases and cancer. J. Clin. Virol. 41, 218–223 (2008).

    PubMed  Article  CAS  Google Scholar 

  205. Cinatl, J. Jr, Vogel, J. U., Kotchetkov, R. & Wilhelm Doerr, H. Oncomodulatory signals by regulatory proteins encoded by human cytomegalovirus: a novel role for viral infection in tumor progression. FEMS Microbiol Rev. 28, 59–77 (2004).

    CAS  PubMed  Article  Google Scholar 

  206. Michaelis, M., Kotchetkov, R., Vogel, J. U., Doerr, H. W. & Cinatl, J. Jr. Cytomegalovirus infection blocks apoptosis in cancer cells. Cell. Mol. Life Sci. 61, 1307–1316 (2004).

    CAS  PubMed  Article  Google Scholar 

  207. Maussang, D. et al. Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesis. Proc. Natl Acad. Sci. USA 103, 13068–13073 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  208. Maussang, D. et al. The human cytomegalovirus-encoded chemokine receptor US28 promotes angiogenesis and tumor formation via cyclooxygenase-2. Cancer Res. 69, 2861–2869 (2009). Together with reference 207, shows the mechanisms of the cytomegalovirus-encoded US28 in promoting tumour formation and angiogenesis.

    CAS  PubMed  Article  Google Scholar 

  209. Alkhalfioui, F., Magnin, T. & Wagner, R. From purified GPCRs to drug discovery: the promise of protein-based methodologies. Curr. Opin. Pharmacol. 9, 629–635 (2009).

    CAS  PubMed  Article  Google Scholar 

  210. Congreve, M. & Marshall, F. The impact of GPCR structures on pharmacology and structure-based drug design. Br. J. Pharmacol. 159, 986–996 (2010).

    CAS  PubMed  Article  Google Scholar 

  211. Cabrera-Vera, T. M. et al. Insights into G protein structure, function, and regulation. Endocr. Rev. 24, 765–781 (2003).

    CAS  PubMed  Article  Google Scholar 

  212. Hurst, J. H. & Hooks, S. B. Regulator of G-protein signaling (RGS) proteins in cancer biology. Biochem. Pharmacol. 78, 1289–1297 (2009).

    CAS  PubMed  Article  Google Scholar 

  213. Hurst, J. H., Mendpara, N. & Hooks, S. B. Regulator of G-protein signalling expression and function in ovarian cancer cell lines. Cell. Mol. Biol. Lett. 14, 153–174 (2009).

    CAS  PubMed  Article  Google Scholar 

  214. Manzur, M., Hamzah, J. & Ganss, R. Modulation of G protein signaling normalizes tumor vessels. Cancer Res. 69, 396–399 (2009).

    CAS  PubMed  Article  Google Scholar 

  215. Ribas, C. et al. The G protein-coupled receptor kinase (GRK) interactome: role of GRKs in GPCR regulation and signaling. Biochim. Biophys. Acta 1768, 913–922 (2007).

    CAS  PubMed  Article  Google Scholar 

  216. Luttrell, L. M. & Gesty-Palmer, D. Beyond desensitization: physiological relevance of arrestin-dependent signaling. Pharmacol. Rev. 62, 305–330 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  217. Pampillo, M. et al. Regulation of GPR54 signaling by GRK2 and b-arrestin. Mol. Endocrinol. 23, 2060–2074 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  218. Baameur, F. et al. Role for the regulator of G-protein signaling homology domain of G protein-coupled receptor kinases 5 and 6 in b 2-adrenergic receptor and rhodopsin phosphorylation. Mol. Pharmacol. 77, 405–415 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

This work was supported by funds from the Associazione Italiana Ricerca sul Cancro (project 8925/2010) and from the Ministero dell'Istruzione, dell'Università e della Ricerca (project PRIN 2008PK2WCW/2008).

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Correspondence to Marcello Maggiolini.

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Glossary

Angiogenesis

The growth of new blood vessels from pre-existing vessels. It is a fundamental step towards an aggressive tumour phenotype.

Metastasis

The ability of cancer cells to penetrate into lymphatic and blood vessels, circulate through the bloodstream and then invade and grow in normal tissues.

Transactivation

Stimulation of gene transcription by transcription factors that can bind to DNA.

Transformed cells

Cells that acquire the properties and behaviour of cancer cells.

Nontransformed cells

Cells that have regular features.

Epithelial-to-mesenchymal transition

A process characterized by the loss of cell adhesion and increased cell mobility, which can occur during embryonic development and in the malignant transformation of cells.

Focal adhesion kinase

A non-receptor tyrosine kinase that resides at the sites of integrin clustering, which are known as focal adhesions. It plays an important part in cell proliferation and migration, as well as in tumour growth, invasion and survival.

Paxillin

A focal adhesion-associated adaptor protein that facilitates the assembly of multi-protein complexes involved in the activation of signalling pathways that lead to cell migration and survival.

Amphiregulin

A member of the epidermal growth factor family that interacts with the epidermal growth factor receptor to regulate the growth of normal and transformed cells.

Cyclin D1

A member of the cyclin family that is required for cell cycle G1/S transition. Mutations, amplification and overexpression of cyclin D1 contribute to tumorigenesis and are observed frequently in various tumours.

Stroma

The supportive framework of an organ, gland or other structure, usually composed of connective tissue.

Anchorage independent proliferation

The proliferation of cells that are unattached to a substrate. Such proliferation can occur in cancer cells and contribute to metastasis.

Primary resistance

Lack of efficacy of a drug (or drugs) in patients who had never received treatment with that drug (or drugs).

Acquired resistance

A lack of efficacy of a drug (or drugs) that initially elicited a response.

Endothelial differentiation genes

Genes that encode G protein-coupled receptors for lysophosphatidic acid or the lysophospholipid mediator sphingosine 1-phosphate.

Diastereomer

An isomer that is a stereoisomer of a compound with two or more chiral centres and that is not a mirror image of another stereoisomer of the same compound.

μNeoplastic tissue

An abnormal mass of tissue that is generated by uncoordinated and excessive cell proliferation that persists after cessation of the stimuli.

Herpes viruses

A large family of DNA viruses that can infect and cause illness in humans.

Kaposi's sarcoma

Cancer characterized by numerous bluish-red nodules on the skin, the development of which is mainly caused by human herpes virus 8 (also known as Kaposi's sarcoma-associated herpes virus).

Burkitt's lymphoma

A non-Hodgkin's lymphoma (also called B cell lymphoma) that is associated with the Epstein–Barr virus.

Hodgkin's disease

A type of lymphoma that originates in lymph nodes and spreads to the spleen, liver and bone marrow.

β2-microglobulin

A component of major histocompatibility complex class I molecules that acts as an oncogenic factor capable of stimulating the growth and invasion of various types of tumour.

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Lappano, R., Maggiolini, M. G protein-coupled receptors: novel targets for drug discovery in cancer. Nat Rev Drug Discov 10, 47–60 (2011). https://doi.org/10.1038/nrd3320

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