Advertisement

Cabazitaxel inhibits prostate cancer cell growth by inhibition of androgen receptor and heat shock protein expression

  • Anja-Martina Rottach
  • Hannes Ahrend
  • Benedikt Martin
  • Reinhard Walther
  • Uwe Zimmermann
  • Martin Burchardt
  • Matthias B. StopeEmail author
Original Article
  • 62 Downloads

Abstract

Purpose

Cabazitaxel, a semi-synthetic taxane of the third generation, inhibits prostate cancer (PC) cell growth by affecting the microtubule architecture. Since cabazitaxel has also been demonstrated to inhibit androgen receptor (AR) functionality, AR and AR-associated heat shock protein (HSP) expressions in the presence of cabazitaxel were characterized.

Methods

AR and HSP expressions were assessed via Western blotting utilizing a PC-cell-line in vitro system incubated with cabazitaxel.

Results

Incubation experiments with 0.3 nM cabazitaxel exhibited significantly reduced levels of AR and the AR-associated factors HSP90α, HSP40, and HSP70/HSP90 organising protein. Furthermore, expression of the anti-apoptotic factor HSP60 was suppressed. In contrast to other anticancer compounds, cabazitaxel did not alter the cytoprotective chemoresistance factor HSP27.

Conclusions

Despite the deregulation of microtubule organisation, cabazitaxel has been shown to suppress the expression of HSP. Very notably, and may be as a result of down-regulated HSP, cabazitaxel additionally inhibits the expression of the AR in AR-positive PC cells. Thus, cabazitaxel bears an additional anti-proliferative activity which is at least in part specific for PC cells.

Keywords

Prostate cancer Cabazitaxel Chemoresistance Androgen receptor Heat shock proteins 

Abbreviations

PC

Prostate cancer

AR

Androgen receptor

GAPDH

Glyceraldehyde 3-phosphate dehydrogenase

ADT

Androgen deprivation therapy

CRPC

Castration-resistant prostate cancer

PSA

Prostate-specific antigen

HSP

Heat shock protein

HOP

HSP70/HSP90-organising protein

SDS-PAGE

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

Notes

Acknowledgements

The authors thank Anne Brandenburg and Katja Wittig for excellent technical assistance.

Author’s contribution

AMR data collection and protocol development. HA data collection. BM data collection. RW data analysis and manuscript editing. UZ manuscript editing and data analysis. MB data analysis and manuscript editing. MBS protocol development, project management, data analysis, manuscript writing, and editing.

Compliance with ethical standards

Conflict of interest

By way of disclosure of conflict of interest, the compound cabazitaxel was kindly provided by Sanofi-Aventis Deutschland GmbH (Frankfurt/Main, Germany). The preparation of the manuscript for the present publication was financially supported by the company Sanofi-Aventis Deutschland GmbH. Sanofi-Aventis Deutschland GmbH has no influence on the published content. The authors alone are responsible for the scientific content of this publication.

Ethical standards

The manuscript does not contain clinical studies or patient data.

References

  1. 1.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108CrossRefGoogle Scholar
  2. 2.
    Center MM, Jemal A, Lortet-Tieulent J, Ward E, Ferlay J, Brawley O, Bray F (2012) International variation in prostate cancer incidence and mortality rates. Eur Urol 61:1079–1092CrossRefGoogle Scholar
  3. 3.
    DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL, Alteri R, Robbins AS, Jemal A (2014) Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin 64:252–271CrossRefGoogle Scholar
  4. 4.
    Huggins C, Hodges CV (1941) Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1:293–297Google Scholar
  5. 5.
    The Medical Research Council Prostate Cancer Working Party Investigators Group (1997) Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. Br J Urol 79:235–246CrossRefGoogle Scholar
  6. 6.
    Seidenfeld J, Samson DJ, Hasselblad V, Aronson N, Albertsen PC, Bennett CL, Wilt TJ (2000) Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis. Ann Intern Med 132:566–577CrossRefGoogle Scholar
  7. 7.
    Katzenwadel A, Wolf P (2015) Androgen deprivation of prostate cancer: leading to a therapeutic dead end. Cancer Lett 367:12–17CrossRefGoogle Scholar
  8. 8.
    Yu EY, Gulati R, Telesca D, Jiang P, Tam S, Russell KJ, Nelson PS, Etzioni RD, Higano CS (2010) Duration of first off-treatment interval is prognostic for time to castration resistance and death in men with biochemical relapse of prostate cancer treated on a prospective trial of intermittent androgen deprivation. J Clin Oncol 28:2668–2673CrossRefGoogle Scholar
  9. 9.
    Mottet N, Bellmunt J, Bolla M, Joniau S, Mason M, Matveev V, Schmid HP, Van der Kwast T, Wiegel T, Zattoni F, Heidenreich A (2011) EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol 59:572–583CrossRefGoogle Scholar
  10. 10.
    Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, Oudard S, Theodore C, James ND, Turesson I, Rosenthal MA, Eisenberger MA, Investigators TAX (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502–1512CrossRefGoogle Scholar
  11. 11.
    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 (2004) Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513–1520CrossRefGoogle Scholar
  12. 12.
    Beer TM, Ryan CW, Venner PM, Petrylak DP, Chatta GS, Ruether JD, Chi KN, Young J, Henner WD, Investigators A (2008) Intermittent chemotherapy in patients with metastatic androgen-independent prostate cancer: results from ASCENT, a double-blinded, randomized comparison of high-dose calcitriol plus docetaxel with placebo plus docetaxel. Cancer 112:326–330CrossRefGoogle Scholar
  13. 13.
    Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fossa SD, Chodacki A, Wiechno P, Logue J, Seke M, Widmark A, Johannessen DC, Hoskin P, Bottomley D, James ND, Solberg A, Syndikus I, Kliment J, Wedel S, Boehmer S, Dall’Oglio M, Franzen L, Coleman R, Vogelzang NJ, O’Bryan-Tear CG, Staudacher K, Garcia-Vargas J, Shan M, Bruland OS, Sartor O, Investigators A (2013) Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 369:213–223CrossRefGoogle Scholar
  14. 14.
    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, Investigators C-A (2013) Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 368:138–148CrossRefGoogle Scholar
  15. 15.
    Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, Verjee SS, Jones LA, Hershberg RM (2006) Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24:3089–3094CrossRefGoogle Scholar
  16. 16.
    Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, Wong YN, Hahn N, Kohli M, Cooney MM, Dreicer R, Vogelzang NJ, Picus J, Shevrin D, Hussain M, Garcia JA, DiPaola RS (2015) Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 373:737–746CrossRefGoogle Scholar
  17. 17.
    James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, Ritchie AW, Parker CC, Russell JM, Attard G, de Bono J, Cross W, Jones RJ, Thalmann G, Amos C, Matheson D, Millman R, Alzouebi M, Beesley S, Birtle AJ, Brock S, Cathomas R, Chakraborti P, Chowdhury S, Cook A, Elliott T, Gale J, Gibbs S, Graham JD, Hetherington J, Hughes R, Laing R, McKinna F, McLaren DB, O’Sullivan JM, Parikh O, Peedell C, Protheroe A, Robinson AJ, Srihari N, Srinivasan R, Staffurth J, Sundar S, Tolan S, Tsang D, Wagstaff J, Parmar MK, STAMPEDE investigators (2016) Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 387:1163–1177CrossRefGoogle Scholar
  18. 18.
    Cookson MS, Roth BJ, Dahm P, Engstrom C, Freedland SJ, Hussain M, Lin DW, Lowrance WT, Murad MH, Oh WK, Penson DF, Kibel AS (2013) Castration-resistant prostate cancer: AUA guideline. J Urol 190:429–438CrossRefGoogle Scholar
  19. 19.
    Mottet N, Bellmunt J, Briers E, van den Bergh RCN, Bolla M, van Casteren NJ, Cornford P, Culine S, Joniau S, Lam T, Mason MD, Matveev V, van der Poel H, van der Kwast T, Rouviere O, Wiegel T (2015) Guidelines on prostate cancer. Eur Assoc UrolGoogle Scholar
  20. 20.
    Bahl A, Masson S, Birtle A, Chowdhury S, de Bono J (2014) Second-line treatment options in metastatic castration-resistant prostate cancer: a comparison of key trials with recently approved agents. Cancer Treat Rev 40:170–177CrossRefGoogle Scholar
  21. 21.
    Mezynski J, Pezaro C, Bianchini D, Zivi A, Sandhu S, Thompson E, Hunt J, Sheridan E, Baikady B, Sarvadikar A, Maier G, Reid AH, Mulick Cassidy A, Olmos D, Attard G, de Bono J (2012) Antitumour activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-resistance? Ann Oncol 23:2943–2947CrossRefGoogle Scholar
  22. 22.
    Lavaud P, Gravis G, Legoupil C, Joly F, Oudard S, Priou F, Mourey L, Soulie M, Latorzeff I, Delva R, Krakowski I, Laguerre B, Theodore C, Ferrero JM, Beuzeboc P, Habibian M, Foulon S, Boher JM, Tergemina-Clain G, Fizazi K (2016) Efficacy and tolerance of treatments received beyond progression in men with metastatic hormone-naive prostate cancer treated with androgen deprivation therapy (ADT) with or without docetaxel in the GETUG-AFU 15 phase III trial. J Clin Oncol 34(15 suppl):5080CrossRefGoogle Scholar
  23. 23.
    de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, Gravis G, Bodrogi I, Mackenzie MJ, Shen L, Roessner M, Gupta S, Sartor AO (2010) Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 376:1147–1154CrossRefGoogle Scholar
  24. 24.
    Vrignaud P, Semiond D, Lejeune P, Bouchard H, Calvet L, Combeau C, Riou JF, Commercon A, Lavelle F, Bissery MC (2013) Preclinical antitumor activity of cabazitaxel, a semisynthetic taxane active in taxane-resistant tumors. Clin Cancer Res 19:2973–2983CrossRefGoogle Scholar
  25. 25.
    van Soest RJ, Nieuweboer AJ, de Morree ES, Chitu D, Bergman AM, Goey SH, Bos MM, van der Meer N, Hamberg P, de Wit R, Mathijssen RH, Dutch Uro-Oncology Studygroup (DUOS) (2015) The influence of prior novel androgen receptor targeted therapy on the efficacy of cabazitaxel in men with metastatic castration-resistant prostate cancer. Eur J Cancer 51:2562–2569CrossRefGoogle Scholar
  26. 26.
    de Morree E, van Soest R, Aghai A, de Ridder C, de Bruijn P, Ghobadi Moghaddam-Helmantel I, Burger H, Mathijssen R, Wiemer E, de Wit R, van Weerden W (2016) Understanding taxanes in prostate cancer; importance of intratumoral drug accumulation. Prostate 76:927–936CrossRefGoogle Scholar
  27. 27.
    Darshan MS, Loftus MS, Thadani-Mulero M, Levy BP, Escuin D, Zhou XK, Gjyrezi A, Chanel-Vos C, Shen R, Tagawa ST, Bander NH, Nanus DM, Giannakakou P (2011) Taxane-induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer. Cancer Res 71:6019–6029CrossRefGoogle Scholar
  28. 28.
    Gibbons NB, Watson RW, Coffey RN, Brady HP, Fitzpatrick JM (2000) Heat-shock proteins inhibit induction of prostate cancer cell apoptosis. Prostate 45:58–65CrossRefGoogle Scholar
  29. 29.
    Cornford PA, Dodson AR, Parsons KF, Desmond AD, Woolfenden A, Fordham M, Neoptolemos JP, Ke Y, Foster CS (2000) Heat shock protein expression independently predicts clinical outcome in prostate cancer. Cancer Res 60:7099–7105PubMedGoogle Scholar
  30. 30.
    Hessenkemper W, Baniahmad A (2013) Targeting heat shock proteins in prostate cancer. Curr Med Chem 20:2731–2740CrossRefGoogle Scholar
  31. 31.
    Rocchi P, Beraldi E, Ettinger S, Fazli L, Vessella RL, Nelson C, Gleave M (2005) Increased Hsp27 after androgen ablation facilitates androgen-independent progression in prostate cancer via signal transducers and activators of transcription 3-mediated suppression of apoptosis. Cancer Res 65:11083–11093CrossRefGoogle Scholar
  32. 32.
    Stope MB, Schubert T, Staar D, Ronnau C, Streitborger A, Kroeger N, Kubisch C, Zimmermann U, Walther R, Burchardt M (2012) Effect of the heat shock protein HSP27 on androgen receptor expression and function in prostate cancer cells. World J Urol 30:327–331CrossRefGoogle Scholar
  33. 33.
    Tang D, Khaleque MA, Jones EL, Theriault JR, Li C, Wong WH, Stevenson MA, Calderwood SK (2005) Expression of heat shock proteins and heat shock protein messenger ribonucleic acid in human prostate carcinoma in vitro and in tumors in vivo. Cell Stress Chaperones 10:46–58CrossRefGoogle Scholar
  34. 34.
    Cappello F, Rappa F, David S, Anzalone R, Zummo G (2003) Immunohistochemical evaluation of PCNA, p53, HSP60, HSP10 and MUC-2 presence and expression in prostate carcinogenesis. Anticancer Res 23:1325–1331PubMedGoogle Scholar
  35. 35.
    Castilla C, Congregado B, Conde JM, Medina R, Torrubia FJ, Japon MA, Saez C (2010) Immunohistochemical expression of Hsp60 correlates with tumor progression and hormone resistance in prostate cancer. Urology 76(1017):e1011–e1016Google Scholar
  36. 36.
    Samali A, Cai J, Zhivotovsky B, Jones DP, Orrenius S (1999) Presence of a pre-apoptotic complex of pro-caspase-3, Hsp60 and Hsp10 in the mitochondrial fraction of jurkat cells. EMBO J 18:2040–2048CrossRefGoogle Scholar
  37. 37.
    Xanthoudakis S, Roy S, Rasper D, Hennessey T, Aubin Y, Cassady R, Tawa P, Ruel R, Rosen A, Nicholson DW (1999) Hsp60 accelerates the maturation of pro-caspase-3 by upstream activator proteases during apoptosis. EMBO J 18:2049–2056CrossRefGoogle Scholar
  38. 38.
    Stope MB, Sauermann A, Ronnau C, Zimmermann U, Walther R, Burchardt M (2012) Androgen receptor and heat shock proteins in progression of prostate cancer cells. Int J Clin Pharmacol Ther 50:65–67CrossRefGoogle Scholar
  39. 39.
    Mita AC, Denis LJ, Rowinsky EK, Debono JS, Goetz AD, Ochoa L, Forouzesh B, Beeram M, Patnaik A, Molpus K, Semiond D, Besenval M, Tolcher AW (2009) Phase I and pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 1-hour infusion every 3 weeks in patients with advanced solid tumors. Clin Cancer Res 15:723–730CrossRefGoogle Scholar
  40. 40.
    Zhu ML, Horbinski CM, Garzotto M, Qian DZ, Beer TM, Kyprianou N (2010) Tubulin-targeting chemotherapy impairs androgen receptor activity in prostate cancer. Cancer Res 70:7992–8002CrossRefGoogle Scholar
  41. 41.
    Bai S, Zhang BY, Dong Y (2018) Impact of taxanes on androgen receptor signaling. Asian J Androl.  https://doi.org/10.4103/aja.aja_37_18 [Epub ahead of print]
  42. 42.
    So A, Hadaschik B, Sowery R, Gleave M (2007) The role of stress proteins in prostate cancer. Curr Genomics 8:252–261CrossRefGoogle Scholar
  43. 43.
    Shan YX, Liu TJ, Su HF, Samsamshariat A, Mestril R, Wang PH (2003) Hsp10 and Hsp60 modulate Bcl-2 family and mitochondria apoptosis signaling induced by doxorubicin in cardiac muscle cells. J Mol Cell Cardiol 35:1135–1143CrossRefGoogle Scholar
  44. 44.
    Ghosh JC, Dohi T, Kang BH, Altieri DC (2008) Hsp60 regulation of tumor cell apoptosis. J Biol Chem 283:5188–5194CrossRefGoogle Scholar
  45. 45.
    Stope MB, Weiss M, Preuss M, Streitborger A, Ritter CA, Zimmermann U, Walther R, Burchardt M (2014) Immediate and transient phosphorylation of the heat shock protein 27 initiates chemoresistance in prostate cancer cells. Oncol Rep 32:2380–2386CrossRefGoogle Scholar
  46. 46.
    Grossebrummel H, Peter T, Mandelkow R, Weiss M, Muzzio D, Zimmermann U, Walther R, Jensen F, Knabbe C, Zygmunt M, Burchardt M, Stope MB (2016) 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 48:793–800CrossRefGoogle Scholar
  47. 47.
    Mandelkow R, Weiss M, Brünnert D, Burchardt M, Stope MB (2016) Lysophosphatidic acid receptor isoforms expression in prostate cancer cells is differentially regulated by the CYP17A1 inhibitor abiraterone and depends on the androgen receptor. Adv Mod Oncol Res 2:57–62CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of UrologyUniversity Medicine GreifswaldGreifswaldGermany
  2. 2.Department of Medical Biochemistry and Molecular BiologyUniversity Medicine GreifswaldGreifswaldGermany

Personalised recommendations