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Neuropeptide-stimulated cell migration in prostate cancer cells is mediated by RhoA kinase signaling and inhibited by neutral endopeptidase

Oncogene volume 25, pages 5942–5952 (2006)Cite this article

Abstract

The neuropeptides bombesin and endothelin-1 stimulate prostate cancer (PC) cell migration and invasion (J Clin Invest, 2000; 106: 1399–1407). The intracellular signaling pathways that direct this cell movement are not well delineated. The monomeric GTPase RhoA is required for migration in several cell types including neutrophils, monocytes and fibroblasts. We demonstrate that bombesin-stimulated PC cell migration occurs via the heterotrimeric G-protein-coupled receptors (G-protein) Gα13 subunit leading to activation of RhoA, and Rho-associated coiled-coil forming protein kinase (ROCK). Using siRNA to suppress expression of the three known G-protein α-subunit-associated RhoA guanine nucleotide exchange factors (GEFs), we also show that two of these RhoA GEFs, PDZ-RhoGEF and leukemia-associated RhoGEF (LARG), link bombesin receptors to RhoA in a non-redundant manner in PC cells. We next show that focal adhesion kinase, which activates PDZ-RhoGEF and LARG, is required for bombesin-stimulated RhoA activation. Neutral endopeptidase (NEP) is expressed on normal prostate epithelium whereas loss of NEP expression contributes to PC progression. We also demonstrate that NEP inhibits neuropeptide activation of RhoA. Together, these results establish a contiguous signaling pathway from the bombesin receptor to ROCK in PC cells, and they implicate NEP as a major regulator of neuropeptide-stimulated RhoA in these cells. This work also identifies members of this signaling pathway as potential targets for rational pharmacologic manipulation of neuropeptide-stimulated migration of PC cells.

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Abbreviations

NEP:

neutral endopeptidase 24.11

ET-1:

endothelin-1

PC:

prostate cancer

FAK:

focal adhesion kinase

GEFs:

guanine nucleotide exchange factors

GAPs:

GTPase-activating proteins

GPCRs:

G-protein-coupled receptors

G-protein:

GTP-binding proteins

RGS:

regulator of G-protein signaling

LARG:

leukemia-associated RhoGEF

LPA:

lysophosphatidic acid

References

  • Aprikian AG, Tremblay L, Han K, Chevalier S . (1997). Int J Cancer 72: 498–504.

  • Arai K, Maruyama Y, Nishida M, Tanabe S, Takagahara S, Kozasa T et al. (2003). Mol Pharmacol 63: 478–488.

  • Bourne HR, Sanders DA, McCormick F . (1990). Nature 348: 125–132.

  • Braga V . (2000). Nat Cell Biol 2: E182–E184.

  • Burridge K, Wennerberg K . (2004). Cell 116: 167–179.

  • Chikumi H, Fukuhara S, Gutkind JS . (2002). J Biol Chem 277: 12463–12473.

  • Dai J, Shen R, Sumitomo M, Goldberg JS, Geng Y, Navarro D et al. (2001). Clin Cancer Res 7: 1370–1377.

  • De Lombaert S, Erion MD, Tan J, Blanchard L, el-Chehabi L, Ghai RD et al. (1994). J Med Chem 37: 498–511.

  • Dhanasekaran N, Dermott JM . (1996). Cell Signal 8: 235–245.

  • Etienne-Manneville S, Hall A . (2002). Nature 420: 629–635.

  • Fukuhara S, Chikumi H, Gutkind JS . (2000). FEBS Lett 485: 183–188.

  • Fukuhara S, Chikumi H, Gutkind JS . (2001). Oncogene 20: 1661–1668.

  • Fukuhara S, Murga C, Zohar M, Igishi T, Gutkind JS . (1999). J Biol Chem 274: 5868–5879.

  • Glaven JA, Whitehead IP, Nomanbhoy T, Kay R, Cerione RA . (1996). J Biol Chem 271: 27374–27381.

  • Gohla A, Offermanns S, Wilkie TM, Schultz G . (1999). J Biol Chem 274: 17901–17907.

  • Grant K, Loizidou M, Taylor I . (2003). Br J Cancer 88: 163–166.

  • Hall A . (1998). Science 279: 509–514.

  • Hart MJ, Jiang X, Kozasa T, Roscoe W, Singer WD, Gilman AG et al. (1998). Science 280: 2112–2114.

  • Hart MJ, Sharma S, elMasry N, Qiu RG, McCabe P, Polakis P et al. (1996). J Biol Chem 271: 25452–25458.

  • Hersch E, Huang J, Grider JR, Murthy KS . (2004). Am J Physiol Cell Physiol 287: C1209–C1218.

  • Ishizaki T, Maekawa M, Fujisawa K, Okawa K, Iwamatsu A, Fujita A et al. (1996). EMBO J 15: 1885–1893.

  • Ishizaki T, Naito M, Fujisawa K, Maekawa M, Watanabe N, Saito Y et al. (1997). FEBS Lett 404: 118–124.

  • Ishizaki T, Uehata M, Tamechika I, Keel J, Nonomura K, Maekawa M et al. (2000). Mol Pharmacol 57: 976–983.

  • Iwase A, Shen R, Navarro D, Nanus DM . (2004). J Biol Chem 279: 11898–11905.

  • Jiang Y, Zhang W, Kondo K, Klco JM, StMartin TB, Dufault MR et al. (2003). Mol Cancer Res 1: 453–462.

  • Kajiyama H, Shibata K, Terauchi M, Morita T, Ino K, Mizutani S et al. (2005). Clin Cancer Res 11: 1798–1808.

  • Karnoub AE, Symons M, Campbell SL, Der CJ . (2004). Breast Cancer Res Treat 84: 61–71.

  • Kassis J, Lauffenburger DA, Turner T, Wells A . (2001). Semin Cancer Biol 11: 105–117.

  • Kitamura K, Shiraishi N, Singer WD, Handlogten ME, Tomita K, Miller RT . (1999). Am J Physiol Cell Physiol 276: C930–C937.

  • Kozasa T, Jiang X, Hart MJ, Sternweis PM, Singer WD, Gilman AG et al. (1998). Science 280: 2109–2111.

  • Kurose H . (2003). Life Sci 74: 155–161.

  • Leung T, Chen XQ, Manser E, Lim L . (1996). Mol Cell Biol 16: 5313–5327.

  • Li Z, Hannigan M, Mo Z, Liu B, Lu W, Wu Y et al. (2003). Cell 114: 215–227.

  • Liu B, Wu D . (2003). J Biol Chem 278: 2384–2387.

  • Lummen G, Virchow S, Rumenapp U, Schmidt M, Wieland T, Otto T et al. (1997). Naunyn Schmiedebergs Arch Pharmacol 356: 769–776.

  • Lyons LS, Burnstein KL . (2005). Mol Endocrinol. Epub ahead of print (29 December 2005).

  • Mackay DJG, Hall A . (1998). J Biol Chem 273: 20685–20688.

  • Mao J, Yuan H, Xie W, Wu D . (1998). Proc Natl Acad Sci USA 95: 12973–12976.

  • Matsui T, Amano M, Yamamoto T, Chihara K, Nakafuku M, Ito M et al. (1996). EMBO J 15: 2208–2216.

  • Nagakawa O, Ogasawara M, Fujii H, Murakami K, Murata J, Fuse H et al. (1998). Cancer Lett 133: 27–33.

  • Nagakawa O, Ogasawara M, Murata J, Fuse H, Saiki I . (2001). Int J Urol 8: 65–70.

  • Nakagawa T, Hocart SJ, Schumann M, Tapia JA, Mantey SA, Coy DH et al. (2005). Biochem Pharmacol 69: 579–593.

  • Offermanns S, Mancino V, Revel JP, Simon MI . (1997). Science 275: 533–536.

  • Papandreou CN, Usmani B, Geng Y, Bogenrieder T, Freeman R, Wilk S et al. (1998). Nat Med 4: 50–57.

  • Radhika V, Onesime D, Ha JH, Dhanasekaran N . (2004). J Biol Chem 279: 49406–49413.

  • Rankin S, Morii N, Narumiya S, Rozengurt E . (1994). FEBS Lett 354: 315–319.

  • Reuther GW, Lambert QT, Booden MA, Wennerberg K, Becknell B, Marcucci G et al. (2001). J Biol Chem 276: 27145–27151.

  • Richardson A, Parsons T . (1996). Nature 380: 538–540.

  • Ridley AJ, Hall A . (1992). Cell 70: 389–399.

  • Rosano L, Varmi M, Salani D, Di Castro V, Spinella F, Natali PG et al. (2001). Cancer Res 61: 8340–8346.

  • Rozengurt E . (2002). Trends Endocrinol Metab 13: 128–134.

  • Sander EE, ten Klooster JP, van Delft S, van der Kammen RA, Collard JG . (1999). J Cell Biol 147: 1009–1022.

  • Saurin JC, Fallavier M, Sordat B, Gevrey JC, Chayvialle JA, Abello J . (2002). Cancer Res 62: 4829–4835.

  • Schmidt A, Hall A . (2002). Genes Dev 16: 1587–1609.

  • Shen R, Sumitomo M, Dai J, Harris A, Kaminetzky D, Gao M et al. (2000). Endocrinology 141: 1699–1704.

  • Shipp M, Look A . (1993). Blood 82: 1052–1070.

  • Somlyo AV, Bradshaw D, Ramos S, Murphy C, Myers CE, Somlyo AP . (2000). Biochem Biophys Res Commun 269: 652–659.

  • Strathmann MP, Simon MI . (1991). Proc Natl Acad Sci USA 88: 5582–5586.

  • Sugden PH . (2003). J Mol Cell Cardiol 35: 871–886.

  • Sugimoto N, Takuwa N, Okamoto H, Sakurada S, Takuwa Y . (2003). Mol Cell Biol 23: 1534–1545.

  • Sumitomo M, Milowsky MI, Shen R, Navarro D, Dai J, Asano T et al. (2001). Cancer Res 61: 3294–3298.

  • Sumitomo M, Shen R, Nanus DM . (2005). Biochim Biophys Acta 1751: 52–59.

  • Sumitomo M, Shen R, Walburg M, Dai J, Geng Y, Navarro D et al. (2000). J Clin Invest 106: 1399–1407.

  • Suzuki N, Nakamura S, Mano H, Kozasa T . (2003). Proc Natl Acad Sci USA 100: 733–738.

  • Tangkijvanich P, Tam SP, Yee Jr HF . (2001). Hepatology 33: 74–80.

  • Turner M, Billadeau DD . (2002). Nat Rev Immunol 2: 476–486.

  • Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T et al. (1997). Nature 389: 990–994.

  • Van Aelst L, D'Souza-Schorey C . (1997). Genes Dev 11: 2295–2322.

  • Wang Q, Liu M, Kozasa T, Rothestein JD, Sternweis PC, Neubig RR . (2004a). Methods Enzymol 389: 244–265.

  • Wang Q, Liu M, Kozasa T, Rothstein JD, Sternweis PC, Neubig RR . (2004b). J Biol Chem 279: 28831–28834.

  • Whitehead IP, Khosravi-Far R, Kirk H, Trigo-Gonzalez G, Der CJ, Kay R . (1996). J Biol Chem 271: 18643–18650.

  • Worthylake RA, Lemoine S, Watson JM, Burridge K . (2001). J Cell Biol 154: 147–160.

  • Xu J, Wang F, Van Keymeulen A, Herzmark P, Straight A, Kelly K et al. (2003). Cell 114: 201–214.

  • Yuan J, Slice LW, Rozengurt E . (2001). J Biol Chem 276: 38619–38627.

  • Zhao R, Seither R, Brigle KE, Sharina IG, Wang PJ, Goldman ID . (1997). J Biol Chem 272: 21207–21212.

  • Zhou K, Wang Y, Gorski JL, Nomura N, Collard J, Bokoch GM . (1998). J Biol Chem 273: 16782–16786.

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Acknowledgements

We thank Dr Marc Symons for useful discussions, and Ms Heather Orkin and Lana Winter for secretarial support. This work was supported by NIH Grants CA80240, DK60908, HL04080 (DJL), the Robert H McCooey Memorial Cancer Research Fund and the Alan Rosenberg Memorial Fund.

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Authors and Affiliations

  1. Department of Urology, Urologic Oncology Research Laboratory, Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, NY, USA

    R Zheng, A Iwase, R Shen & D M Nanus

  2. Division of Hematology and Medical Oncology, Department of Medicine, Genitourinary Oncology Research Laboratory, Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, NY, USA

    R Zheng, O B Goodman Jr & D M Nanus

  3. Department of Physiology, Kanazawa University School of Medicine, Takaramachi, Kanazawa, Japan

    N Sugimoto & Y Takuwa

  4. Division of Cardiology, Department of Medicine, Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, NY, USA

    D J Lerner

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Correspondence to D M Nanus.

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Zheng, R., Iwase, A., Shen, R. et al. Neuropeptide-stimulated cell migration in prostate cancer cells is mediated by RhoA kinase signaling and inhibited by neutral endopeptidase. Oncogene 25, 5942–5952 (2006). https://doi.org/10.1038/sj.onc.1209586

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