Introduction: Inhibition of androgen synthesis by abiraterone acetate (AA) entails enhanced overall survival rates and clinical benefit for patients with locally advanced and metastasized prostate cancer (PC). The expression of heat shock protein 27 (HSP27) is generally associated with cytoprotection and was demonstrated to mediate chemoresistance under cytostatic therapy, for instance, docetaxel treatment. In this study, we investigated the impact of AA treatment on HSP27 expression and PC cell growth. Materials and Methods: HSP27 expression levels in docetaxel and AA-treated PC cell lines LNCaP and PC-3 were determined by SDS PAGE and Western blot analysis. Proliferation assays were performed using a CASY Cell Counter and Analyzer Model TT (Roche Applied Science). Results: Despite significantly increased HSP27 expression in PC cells incubated with docetaxel, Western blot analysis implicated a significant reduction of the cytoprotective HSP27 in AA-treated PC cells. Notably, HSP27 stably overexpressed in PC-3-HSP27 cells did not appear as an HSP27-mediated proliferation benefit in the presence of AA as shown in docetaxel incubation studies. Conclusion: In contrast to repeatedly demonstrated HSP27-driven chemoresistance related to chemotherapeutics, our results may constitute a broader molecular mode of action of AA chemotherapy. AA efficacy may exert an HSP27 suppressive role that goes beyond the primarily assumed inhibition of androgen biosynthesis.

Keywords:
Prostate cancer, Abiraterone, Heat shock protein 27, Cytoprotection, Chemotherapy
1.
de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Fléchon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI; COU-AA-301 Investigators: Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364:1995-2005.
2.
Kaku T, Hitaka T, Ojida A, Matsunaga N, Adachi M, Tanaka T, Hara T, Yamaoka M, Kusaka M, Okuda T, Asahi S, Furuya S, Tasaka A: Discovery of orteronel (TAK-700), a naphthylmethylimidazole derivative, as a highly selective 17,20-lyase inhibitor with potential utility in the treatment of prostate cancer. Bioorg Med Chem 2011;19:6383-6399.
3.
Vasaitis T, Belosay A, Schayowitz A, Khandelwal A, Chopra P, Gediya LK, Guo Z, Fang HB, Njar VC, Brodie AM: Androgen receptor inactivation contributes to antitumor efficacy of 17{alpha}-hydroxylase/17,20-lyase inhibitor 3beta-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene in prostate cancer. Mol Cancer Ther 2008;7:2348-2357.
4.
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ: Cancer statistics, 2008. CA Cancer J Clin 2008;58:71-96.
5.
Wu JN, Fish KM, Evans CP, Devere White RW, Dall'Era MA: No improvement noted in overall or cause-specific survival for men presenting with metastatic prostate cancer over a 20-year period. Cancer 2014;120:818-823.
6.
Froehner M, Hölscher T, Hakenberg OW, Wirth MP: Treatment of bone metastases in urologic malignancies. Urol Int 2014;93:249-256.
7.
Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513-1520.
8.
Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Théodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA; TAX 327 Investigators: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-1512.
9.
Logothetis CJ, Gallick GE, Maity SN, Kim J, Aparicio A, Efstathiou E, Lin SH: Molecular classification of prostate cancer progression: foundation for marker-driven treatment of prostate cancer. Cancer Discov 2013;3:849-861.
10.
Turo R, Tan K, Thygesen H, Sundaram SK, Chahal R, Prescott S, Cross WR: Diethylstilboestrol (1 mg) in the management of castration-resistant prostate cancer. Urol Int 2015;94:307-312.
11.
Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, True LD, Nelson PS: Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res 2008;68:4447-4454.
12.
Chang KH, Li R, Papari-Zareei M, Watumull L, Zhao YD, Auchus RJ, Sharifi N: Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer. Proc Natl Acad Sci U S A 2011;108:13728-13733.
13.
Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, Fizazi K, Mainwaring P, Piulats JM, Ng S, Carles J, Mulders PF, Basch E, Small EJ, Saad F, Schrijvers D, Van Poppel H, Mukherjee SD, Suttmann H, Gerritsen WR, Flaig TW, George DJ, Yu EY, Efstathiou E, Pantuck A, Winquist E, Higano CS, Taplin ME, Park Y, Kheoh T, Griffin T, Scher HI, Rathkopf DE; COU-AA-302 Investigators: Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013;368:138-148.
14.
Mostaghel EA, Marck BT, Plymate SR, Vessella RL, Balk S, Matsumoto AM, Nelson PS, Montgomery RB: Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants. Clin Cancer Res 2011;17:5913-5925.
15.
Joseph JD, Lu N, Qian J, Sensintaffar J, Shao G, Brigham D, Moon M, Maneval EC, Chen I, Darimont B, Hager JH: A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov 2013;3:1020-1029.
16.
Gao L, Schwartzman J, Gibbs A, Lisac R, Kleinschmidt R, Wilmot B, Bottomly D, Coleman I, Nelson P, McWeeney S, Alumkal J: Androgen receptor promotes ligand-independent prostate cancer progression through c-Myc upregulation. PLoS One 2013;8:e63563.
17.
Stope MB, Weiss M, Preuss M, Streitbörger A, Ritter CA, Zimmermann U, Walther R, Burchardt M: Immediate and transient phosphorylation of the heat shock protein 27 initiates chemoresistance in prostate cancer cells. Oncol Rep 2014;32:2380-2386.
18.
Ischia J, Saad F, Gleave M: The promise of heat shock protein inhibitors in the treatment of castration resistant prostate cancer. Curr Opin Urol 2013;23:194-200.
19.
Stope MB, Schubert T, Staar D, Rönnau C, Streitbörger A, Kroeger N, Kubisch C, Zimmermann U, Walther R, Burchardt M: Effect of the heat shock protein HSP27 on androgen receptor expression and function in prostate cancer cells. World J Urol 2012;30:327-331.
20.
Stope MB, Stender C, Schubert T, Peters S, Weiss M, Ziegler P, Zimmermann U, Walther R, Burchardt M: Heat-shock protein HSPB1 attenuates microRNA miR-1 expression thereby restoring oncogenic pathways in prostate cancer cells. Anticancer Res 2014;34:3475-3480.
21.
Weiss M, Burchardt M, Stope M: Master of puppets in prostate cancer: heat shock protein 27 is pulling androgen receptor's strings. Can Cell Microenviron 2014;1:e287.
22.
Grossebrummel H, Peter T, Mandelkow R, Weiss M, Muzzio D, Zimmermann U, Walther R, Jensen F, Knabbe C, Zygmunt M, Burchardt M, Stope MB: Cytochrome P450 17A1 inhibitor abiraterone attenuates cellular growth of prostate cancer cells independently from androgen receptor signaling by modulation of oncogenic and apoptotic pathways. Int J Oncol 2016;48:793-800.
23.
Bohrer LR, Chen S, Hallstrom TC, Huang H: Androgens suppress EZH2 expression via retinoblastoma (RB) and p130-dependent pathways: a potential mechanism of androgen-refractory progression of prostate cancer. Endocrinology 2010;151:5136-5145.
24.
Schroeder A, Herrmann A, Cherryholmes G, Kowolik C, Buettner R, Pal S, Yu H, Müller-Newen G, Jove R: Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through STAT3 signaling. Cancer Res 2014;74:1227-1237.
25.
Verras M, Lee J, Xue H, Li TH, Wang Y, Sun Z: The androgen receptor negatively regulates the expression of c-Met: implications for a novel mechanism of prostate cancer progression. Cancer Res 2007;67:967-975.
26.
Kostenko S, Moens U: Heat shock protein 27 phosphorylation: kinases, phosphatases, functions and pathology. Cell Mol Life Sci 2009;66:3289-3307.
27.
Ischia J, Saad F, Gleave M: The promise of heat shock protein inhibitors in the treatment of castration resistant prostate cancer. Curr Opin Urol 2013;23:194-200.
28.
A randomized, double-blind phase 2 study comparing gemcitabine and cisplatin in combination with OGX-427 or placebo in patients with advanced transitional cell carcinoma. http://clinicaltrials.gov/show/NCT01454089.
29.
A randomized phase II study of OGX-427 (a second-generation antisense oligonucleotide to heat shock protein-27) in patients with castration resistant prostate cancer who have not previously received chemotherapy for metastatic disease. http://clinicaltrials.gov/ct2/show/NCT01120470?term=NCT01120470&rank=1.
© 2016 S. Karger AG, Basel
2016
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