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Synuclein γ protects Akt and mTOR and renders tumor resistance to Hsp90 disruption

Oncogene volume 34, pages 2398–2405 (2015)Cite this article

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Abstract

Heat shock protein (Hsp)90 regulates many key pathways in oncogenesis, including Akt and mammalian target of rapamycin (mTOR). The strengths of disruption of Hsp90 in cancer therapy include their versatility in inhibiting a wide range of oncogenic pathways. The present study demonstrated that synuclein γ (SNCG) protects the functions of Akt and mTOR in the condition when the function of Hsp90 is blocked. Disruption of Hsp90 abolished Akt activity and mTOR signaling. However, expression of SNCG restored Akt activity and mTOR signaling. SNCG bound to Akt and mTOR in the presence and absence of Hsp90. Specifically, the C-terminal (Gln106-Asp127) of SNCG bound to the loop connecting αC helix and β4 sheet of the kinase domain of Akt. SNCG renders resistance to 17-AAG-induced apoptosis both in vitro and in tumor xenograft. A clinical follow-up study indicates that patients with an SNCG-positive breast cancer have a significantly shorter disease-free survival and overall survival than patients with SNCG-negative tumors. The present study indicates that SNCG protects Hsp90 client proteins of Akt and mTOR, and renders drug resistance to Hsp90 disruption.

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References

  1. Neckers L . Heat shock protein 90: the cancer chaperone. J Biosci 2007; 32: 517–530.

    Article  CAS  Google Scholar 

  2. Wandinger SK, Richter K, Buchner J . The Hsp90 chaperone machinery. J Biol Chem 2008; 283: 18473.

    Article  CAS  Google Scholar 

  3. Bonvini P, Gastaldi T, Falini B, Rosolen A . Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), a novel Hsp90-client tyrosine kinase: down-regulation of NPM-ALK expression and tyrosine phosphorylation in ALK(+) CD30(+) lymphoma cells by the Hsp90 antagonist 17-allylamino,17-demethoxygeldanamycin. Cancer Res 2002; 62: 1559–1566.

    CAS  Google Scholar 

  4. Nimmanapalli R, O'Bryan E, Bhalla K . Geldanamycin and its analogue 17-allylamino-17-demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of Bcr-Abl-positive human leukemic blasts. Cancer Res 2001; 61: 1799–1804.

    CAS  Google Scholar 

  5. Chiosis G, Timaul MN, Lucas B, Munster PN, Zheng FF, Sepp-Lorenzino L et al. A small molecule designed to bind to the adenine nucleotide pocket of Hsp90 causes Her2 degradation and the growth arrest and differentiation of breast cancer cells. Chem Biol 2001; 8: 289–299.

    Article  CAS  Google Scholar 

  6. Caldas-Lopes E, Cerchietti L, Ahn JH, Clement CC, Robles AI, Rodina A et al. Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer models. Proc Natl Acad Sci USA 2009; 106: 8368–8373.

    Article  CAS  Google Scholar 

  7. Workman P, Burrows F, Neckers L, Rosen N . Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress. Ann NY Acad Sci 2007; 1113: 202–216.

    Article  CAS  Google Scholar 

  8. Gaspar N, Sharp SY, Pacey S, Jones C, Walton M, Vassal G et al. Acquired resistance to 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) in glioblastoma cells. Cancer Res 2009; 69: 1966–1975.

    Article  CAS  Google Scholar 

  9. McCollum AK, Teneyck CJ, Sauer BM, Toft DO, Erlichman C . Up-regulation of heat shock protein 27 induces resistance to 17-allylamino-demethoxygeldanamycin through a glutathione-mediated mechanism. Cancer Res 2006; 66: 10967–10975.

    Article  CAS  Google Scholar 

  10. Ji H, Liu YE, Jia T, Wang M, Liu J, Xiao G et al. Identification of a breast cancer-specific gene, BCSG1, by direct differential cDNA sequencing. Cancer Res 1997; 57: 759–764.

    CAS  Google Scholar 

  11. Clayton DF, George JM . The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease. Trends Neurosci 1998; 21: 249–254.

    Article  CAS  Google Scholar 

  12. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 1997; 276: 2045–2047.

    Article  CAS  Google Scholar 

  13. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M . Alpha-synuclein in Lewy bodies. Nature 1997; 388: 839–840.

    Article  CAS  Google Scholar 

  14. Bruening W, Giasson BI, Klein-Szanto AJ, Lee VM, Trojanowski JQ, Godwin AK . Synucleins are expressed in the majority of breast and ovarian carcinomas and in preneoplastic lesions of the ovary. Cancer 2000; 88: 2154–2163.

    Article  CAS  Google Scholar 

  15. Wu K, Weng Z, Tao Q, Lin G, Wu X, Qian H et al. Stage-specific expression of breast cancer-specific gene gamma-synuclein. Cancer Epidemiol Biomarkers Prev 2003; 12: 920–925.

    CAS  Google Scholar 

  16. Guo J, Shou C, Meng L, Jiang B, Dong B, Yao L et al. Neuronal protein synuclein gamma predicts poor clinical outcome in breast cancer. Int J Cancer 2007; 121: 1296–1305.

    Article  CAS  Google Scholar 

  17. Liu H, Liu W, Wu Y, Zhou Y, Xue R, Luo C et al. Loss of epigenetic control of synuclein-gamma gene as a molecular indicator of metastasis in a wide range of human cancers. Cancer Res 2005; 65: 7635–7643.

    Article  CAS  Google Scholar 

  18. Zhao W, Liu H, Liu W, Wu Y, Chen W, Jiang B et al. Abnormal activation of the synuclein-gamma gene in hepatocellular carcinomas by epigenetic alteration. Int J Oncol 2006; 28: 1081–1088.

    CAS  Google Scholar 

  19. Liu C, Guo J, Qu L, Bing D, Meng L, Wu J et al. Applications of novel monoclonal antibodies specific for synuclein-gamma in evaluating its levels in sera and cancer tissues from colorectal cancer patients. Cancer Lett 2008; 269: 148–158.

    Article  CAS  Google Scholar 

  20. Liu C, Dong B, Lu A, Qu L, Xing X, Meng L et al. Synuclein gamma predicts poor clinical outcome in colon cancer with normal levels of carcinoembryonic antigen. BMC Cancer 2010; 10: 359.

    Article  Google Scholar 

  21. Hu H, Sun L, Guo C, Liu Q, Zhou Z, Peng L et al. Tumor cell-microenvironment interaction models coupled with clinical validation reveal CCL2 and SNCG as two predictors of colorectal cancer hepatic metastasis. Clin Cancer Res 2009; 15: 5485–5493.

    Article  CAS  Google Scholar 

  22. Li Z, Sclabas GM, Peng B, Hess KR, Abbruzzese JL, Evans DB et al. Overexpression of synuclein-gamma in pancreatic adenocarcinoma. Cancer 2004; 101: 58–65.

    Article  CAS  Google Scholar 

  23. Hibi T, Mori T, Fukuma M, Yamazaki K, Hashiguchi A, Yamada T et al. Synuclein-gamma is closely involved in perineural invasion and distant metastasis in mouse models and is a novel prognostic factor in pancreatic cancer. Clin Cancer Res 2009; 15: 2864–2871.

    Article  CAS  Google Scholar 

  24. Iwaki H, Kageyama S, Isono T, Wakabayashi Y, Okada Y, Yoshimura K et al. Diagnostic potential in bladder cancer of a panel of tumor markers (calreticulin, gamma -synuclein, and catechol-o-methyltransferase) identified by proteomic analysis. Cancer Sci 2004; 95: 955–961.

    Article  CAS  Google Scholar 

  25. Czekierdowski A, Czekierdowska S, Wielgos M, Smolen A, Kaminski P, Kotarski J . The role of CpG islands hypomethylation and abnormal expression of neuronal protein synuclein-gamma (SNCG) in ovarian cancer. Neuro Endocrinol Lett 2006; 27: 381–386.

    CAS  Google Scholar 

  26. Fung KM, Rorke LB, Giasson B, Lee VM, Trojanowski JQ . Expression of alpha-, beta-, and gamma-synuclein in glial tumors and medulloblastomas. Acta Neuropathol 2003; 106: 167–175.

    Article  CAS  Google Scholar 

  27. Jia T, Liu YE, Liu J, Shi YE . Stimulation of breast cancer invasion and metastasis by synuclein gamma. Cancer Res 1999; 59: 742–747.

    CAS  Google Scholar 

  28. Jiang Y, Liu YE, Lu A, Gupta A, Goldberg ID, Liu J et al. Stimulation of estrogen receptor signaling by gamma synuclein. Cancer Res 2003; 63: 3899–3903.

    CAS  Google Scholar 

  29. Jiang Y, Liu YE, Goldberg ID, Shi YE . Gamma synuclein, a novel heat-shock protein-associated chaperone, stimulates ligand-dependent estrogen receptor alpha signaling and mammary tumorigenesis. Cancer Res 2004; 64: 4539–4546.

    Article  CAS  Google Scholar 

  30. Gupta A, Inaba S, Wong OK, Fang G, Liu J . Breast cancer-specific gene 1 interacts with the mitotic checkpoint kinase BubR1. Oncogene 2003; 22: 7593–7599.

    Article  CAS  Google Scholar 

  31. Inaba S, Li C, Shi YE, Song DQ, Jiang JD, Liu J . Synuclein gamma inhibits the mitotic checkpoint function and promotes chromosomal instability of breast cancer cells. Breast Cancer Res Treat 2005; 94: 25–35.

    Article  CAS  Google Scholar 

  32. Liu YE, Pu W, Jiang Y, Shi D, Dackour R, Shi YE . Chaperoning of estrogen receptor and induction of mammary gland proliferation by neuronal protein synuclein gamma. Oncogene 2007; 26: 2115–2125.

    Article  CAS  Google Scholar 

  33. Shi YE, Chen Y, Dackour R, Potters L, Wang S, Ding Q et al. Synuclein gamma stimulates membrane-initiated estrogen signaling by chaperoning estrogen receptor (ER)-alpha36, a variant of ER-alpha. Am J Pathol 2010; 177: 964–973.

    Article  CAS  Google Scholar 

  34. Citri A, Harari D, Shohat G, Ramakrishnan P, Gan J, Lavi S et al. Hsp90 recognizes a common surface on client kinases. J Biol Chem 2006; 281: 14361–14369.

    Article  CAS  Google Scholar 

  35. Manivel P, Muthukumaran J, Kannan M, Krishna R . Insight into residues involved in the structure and function of the breast cancer associated protein human gamma synuclein. J Mol Model 2011; 17: 251–263.

    Article  CAS  Google Scholar 

  36. Hua H, Xu L, Wang J, Jing J, Luo T, Jiang Y . Up-regulation of gamma-synuclein contributes to cancer cell survival under endoplasmic reticulum stress. J Pathol 2009; 217: 507–515.

    Article  CAS  Google Scholar 

  37. Solit DB, Basso AD, Olshen AB, Scher HI, Rosen N . Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol. Cancer Res 2003; 63: 2139–2144.

    CAS  Google Scholar 

  38. Souza JM, Giasson BI, Lee VM, Ischiropoulos H . Chaperone-like activity of synucleins. FEBS Lett 2000; 474: 116–119.

    Article  CAS  Google Scholar 

  39. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006; 66: 1500–1508.

    Article  CAS  Google Scholar 

  40. Wullschleger S, Loewith R, Hall MN . TOR signaling in growth and metabolism. Cell 2006; 124: 471–484.

    Article  CAS  Google Scholar 

  41. Okawa Y, Hideshima T, Steed P, Vallet S, Hall S, Huang K et al. SNX-2112, a selective Hsp90 inhibitor, potently inhibits tumor cell growth, angiogenesis, and osteoclastogenesis in multiple myeloma and other hematologic tumors by abrogating signaling via Akt and ERK. Blood 2009; 113: 846–855.

    Article  CAS  Google Scholar 

  42. Pan ZZ, Bruening W, Giasson BI, Lee VM, Godwin AK . Gamma-synuclein promotes cancer cell survival and inhibits stress- and chemotherapy drug-induced apoptosis by modulating MAPK pathways. J Biol Chem 2002; 277: 35050–35060.

    Article  CAS  Google Scholar 

  43. Taiyab A, Sreedhar AS, Rao Ch M . Hsp90 inhibitors, GA and 17AAG, lead to ER stress-induced apoptosis in rat histiocytoma. Biochem Pharmacol 2009; 78: 142–152.

    Article  CAS  Google Scholar 

  44. Davenport EL, Moore HE, Dunlop AS, Sharp SY, Workman P, Morgan GJ et al. Heat shock protein inhibition is associated with activation of the unfolded protein response pathway in myeloma plasma cells. Blood 2007; 110: 2641–2649.

    Article  CAS  Google Scholar 

  45. Szegezdi E, Logue SE, Gorman AM, Samali A . Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep 2006; 7: 880–885.

    Article  CAS  Google Scholar 

  46. Yang J, Cron P, Thompson V, Good VM, Hess D, Hemmings BA et al. Molecular mechanism for the regulation of protein kinase B/Akt by hydrophobic motif phosphorylation. Mol Cell 2002; 9: 1227–1240.

    Article  CAS  Google Scholar 

  47. Pan ZZ, Bruening W, Godwin AK . Involvement of RHO GTPases and ERK in synuclein-gamma enhanced cancer cell motility. Int J Oncol 2006; 29: 1201–1205.

    CAS  Google Scholar 

  48. Singh VK, Zhou Y, Marsh JA, Uversky VN, Forman-Kay JD, Liu J et al. Synuclein-gamma targeting peptide inhibitor that enhances sensitivity of breast cancer cells to antimicrotubule drugs. Cancer Res 2007; 67: 626–633.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported in part by grants 81230054 and 91029739 from the State Key Program of National Natural Science Foundation of China; a grant from the National Key Technology R&D Program for the 12th Five-year Plan of China (2013BAI01B06); and a grant from the State Key Laboratory of Reproductive Medicine, and a Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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Authors and Affiliations

  1. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    W Liang, S Miao, B Zhang, S He & Y E Shi

  2. Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, China

    C Shou

  3. Centre for Bioinformatics, School of Life Science, Pondicherry University, Puducherry, India

    P Manivel & R Krishna

  4. Department of Surgery, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Y Chen

  5. State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China,

    Y E Shi

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  1. W Liang
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Correspondence to Y Chen or Y E Shi.

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Liang, W., Miao, S., Zhang, B. et al. Synuclein γ protects Akt and mTOR and renders tumor resistance to Hsp90 disruption. Oncogene 34, 2398–2405 (2015). https://doi.org/10.1038/onc.2014.126

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