Hsp27 Regulates Epithelial Mesenchymal Transition, Metastasis, and Circulating Tumor Cells in Prostate Cancer (original) (raw)

Abstract

Defining the mechanisms underlying metastatic progression of prostate cancer may lead to insights into how to decrease morbidity and mortality in this disease. An important determinant of metastasis is epithelial-tomesenchymal transition (EMT), and the mechanisms that control the process of EMT in cancer cells are still emerging. Here, we report that the molecular chaperone Hsp27 (HSPB1) drives EMT in prostate cancer, whereas its attenuation reverses EMT and decreases cell migration, invasion, and matrix metalloproteinase activity. Mechanistically, silencing Hsp27 decreased IL-6-dependent STAT3 phosphorylation, nuclear translocation, and STAT3 binding to the Twist promoter, suggesting that Hsp27 is required for IL-6-mediated EMT via modulation of STAT3/Twist signaling. We observed a correlation between Hsp27 and Twist in patients with prostate cancer, with Hsp27 and Twist expression each elevated in high-grade prostate cancer tumors. Hsp27 inhibition by OGX-427, an antisense therapy currently in phase II trials, reduced tumor metastasis in a murine model of prostate cancer. More importantly, OGX-427 treatment decreased the number of circulating tumor cells in patients with metastatic castration-resistant prostate cancer in a phase I clinical trial. Overall, this study defines Hsp27 as a critical regulator of IL-6-dependent and IL-6-independent EMT, validating this chaperone as a therapeutic target to treat metastatic prostate cancer. Cancer Res; 73(10); 3109-19. Ó2013 AACR.

Loading...

Loading Preview

Sorry, preview is currently unavailable. You can download the paper by clicking the button above.

References (43)

  1. Gleave ME, Goldenberg SL, Chin JL, Warner J, Saad F, Klotz LH, et al. Randomized comparative study of 3 versus 8-month neoadjuvant hormonal therapy before radical prostatectomy: biochemical and pathological effects. J Urol 2001;166:500-6.
  2. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell 2009;139:871-90.
  3. Yadav A, Kumar B, Datta J, Teknos TN, Kumar P. IL-6 promotes head and neck tumor metastasis by inducing epithelial-mesenchymal transition via the JAK-STAT3-SNAIL signaling pathway. Mol Cancer Res 2011;9:1658-67.
  4. Yao Z, Fenoglio S, Gao DC, Camiolo M, Stiles B, Lindsted T, et al. TGF- beta IL-6 axis mediates selective and adaptive mechanisms of resis- tance to molecular targeted therapy in lung cancer. Proc Natl Acad Sci U S A 2010;107:15535-40.
  5. Sullivan NJ, Sasser AK, Axel AE, Vesuna F, Raman V, Ramirez N, et al. Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene 2009;28:2940-7.
  6. Drachenberg DE, Elgamal AA, Rowbotham R, Peterson M, Murphy GP. Circulating levels of interleukin-6 in patients with hormone refractory prostate cancer. Prostate 1999;41:127-33.
  7. Rocchi P, Beraldi E, Ettinger S, Fazli L, Vessella RL, Nelson C, et al. Increased Hsp27 after androgen ablation facilitates androgen-inde- pendent progression in prostate cancer via signal transducers and activators of transcription 3-mediated suppression of apoptosis. Can- cer Res 2005;65:11083-93.
  8. Tenniswood MP, Guenette RS, Lakins J, Mooibroek M, Wong P, Welsh JE. Active cell death in hormone-dependent tissues. Cancer Metas- tasis Rev 1992;11:197-220.
  9. Paul C, Manero F, Gonin S, Kretz-Remy C, Virot S, Arrigo AP. Hsp27 as a negative regulator of cytochrome C release. Mol Cell Biol 2002;22:816-34.
  10. Zoubeidi A, Gleave M. Small heat shock proteins in cancer therapy and prognosis. Int J Biochem Cell Biol 2012;44:1646-56.
  11. Garrido C, Bruey JM, Fromentin A, Hammann A, Arrigo AP, Solary E. HSP27 inhibits cytochrome c-dependent activation of procaspase-9. FASEB J 1999;13:2061-70.
  12. Zoubeidi A, Zardan A, Wiedmann RM, Locke J, Beraldi E, Fazli L, et al. Hsp27 promotes insulin-like growth factor-I survival signaling in pros- tate cancer via p90Rsk-dependent phosphorylation and inactivation of BAD. Cancer Res 2010;70:2307-17.
  13. Bausero MA, Bharti A, Page DT, Perez KD, Eng JW, Ordonez SL, et al. Silencing the hsp25 gene eliminates migration capability of the highly metastatic murine 4T1 breast adenocarcinoma cell. Tumour Biol 2006;27:17-26.
  14. Mizutani H, Okano T, Minegishi Y, Matsuda K, Sudoh J, Kitamura K, et al. HSP27 modulates epithelial to mesenchymal transition of lung cancer cells in a Smad-independent manner. Oncol Lett 2010;1:1011-6.
  15. Vidyasagar A, Reese S, Acun Z, Hullett D, Djamali A. HSP27 is involved in the pathogenesis of kidney tubulointerstitial fibrosis. Am J Physiol Renal Physiol 2008;295:F707-16.
  16. Song H, Ethier SP, Dziubinski ML, Lin J. Stat3 modulates heat shock 27kDa protein expression in breast epithelial cells. Biochem Biophys Res Commun 2004;314:143-50.
  17. Zhau HE, Odero-Marah V, Lue HW, Nomura T, Wang R, Chu G, et al. Epithelial to mesenchymal transition (EMT) in human prostate cancer: lessons learned from ARCaP model. Clin Exp Metastasis 2008;25: 601-10.
  18. Xu J, Wang R, Xie ZH, Odero-Marah V, Pathak S, Multani A, et al. Prostate cancer metastasis: role of the host microenvironment in promoting epithelial to mesenchymal transition and increased bone and adrenal gland metastasis. Prostate 2006;66:1664-73.
  19. Cheng GZ, Zhang WZ, Sun M, Wang Q, Coppola D, Mansour M, et al. Twist is transcriptionally induced by activation of STAT3 and mediates STAT3 oncogenic function. J Biol Chem 2008;283:14665-73.
  20. Bruey JM, Paul C, Fromentin A, Hilpert S, Arrigo AP, Solary E, et al. Differential regulation of HSP27 oligomerization in tumor cells grown in vitro and in vivo. Oncogene 2000;19:4855-63.
  21. Conroy SE, Sasieni PD, Amin V, Wang DY, Smith P, Fentiman IS, et al. Antibodies to heat-shock protein 27 are associated with improved survival in patients with breast cancer. Br J Cancer 1998;77:1875-9.
  22. Foster CS, Dodson AR, Ambroisine L, Fisher G, Moller H, Clark J, et al. Hsp-27 expression at diagnosis predicts poor clinical outcome in prostate cancer independent of ETS-gene rearrangement. Br J Cancer 2009;101:1137-44.
  23. Garrido C, Fromentin A, Bonnotte B, Favre N, Moutet M, Arrigo AP, et al. Heat shock protein 27 enhances the tumorigenicity of immu- nogenic rat colon carcinoma cell clones. Cancer Res 1998;58: 5495-9.
  24. Rocchi P, So A, Kojima S, Signaevsky M, Beraldi E, Fazli L, et al. Heat shock protein 27 increases after androgen ablation and plays a cytoprotective role in hormone-refractory prostate cancer. Cancer Res 2004;64:6595-602.
  25. Lee JW, Kwak HJ, Lee JJ, Kim YN, Park MJ, Jung SE, et al. HSP27 regulates cell adhesion and invasion via modulation of focal adhesion kinase and MMP-2 expression. Eur J Cell Biol 2008;87:377-87.
  26. Graham TR, Zhau HE, Odero-Marah VA, Osunkoya AO, Kimbro KS, Tighiouart M, et al. Insulin-like growth factor-I-dependent up-regula- tion of ZEB1 drives epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer Res 2008;68:2479-88.
  27. Kostenko S, Johannessen M, Moens U. PKA-induced F-actin rear- rangement requires phosphorylation of Hsp27 by the MAPKAP kinase MK5. Cell Signal 2009;21:712-8.
  28. Chen P, Parks WC. Role of matrix metalloproteinases in epithelial migration. J Cell Biochem 2009;108:1233-43.
  29. Adler HL, McCurdy MA, Kattan MW, Timme TL, Scardino PT, Thomp- son TC. Elevated levels of circulating interleukin-6 and transforming growth factor-beta1 in patients with metastatic prostatic carcinoma. J Urol 1999;161:182-7.
  30. Scher HI, Jia X, de Bono JS, Fleisher M, Pienta KJ, Raghavan D, et al. Circulating tumour cells as prognostic markers in progressive, cas- tration-resistant prostate cancer: a reanalysis of IMMC38 trial data. Lancet Oncol 2009;10:233-9.
  31. Arts HJ, Hollema H, Lemstra W, Willemse PH, De Vries EG, Kampinga HH, et al. Heat-shock-protein-27 (hsp27) expression in ovarian carci- noma: relation in response to chemotherapy and prognosis. Int J Cancer 1999;84:234-8.
  32. Zhang R, Tremblay TL, McDermid A, Thibault P, Stanimirovic D. Identification of differentially expressed proteins in human glioblasto- ma cell lines and tumors. Glia 2003;42:194-208.
  33. Bubendorf L, Kolmer M, Kononen J, Koivisto P, Mousses S, Chen Y, et al. Hormone therapy failure in human prostate cancer: analysis by complementary DNA and tissue microarrays. J Natl Cancer Inst 1999;91:1758-64.
  34. Cornford PA, Dodson AR, Parsons KF, Desmond AD, Woolfenden A, Fordham M, et al. Heat shock protein expression independently predicts clinical outcome in prostate cancer. Cancer Res 2000;60:7099-105.
  35. Wei L, Liu TT, Wang HH, Hong HM, Yu AL, Feng HP, et al. Hsp27 participates in the maintenance of breast cancer stem cells through regulation of epithelial-mesenchymal transition and nuclear factor- kappaB. Breast Cancer Res 2011;13:R101.
  36. Nakashima J, Tachibana M, Horiguchi Y, Oya M, Ohigashi T, Asakura H, et al. Serum interleukin 6 as a prognostic factor in patients with prostate cancer. Clin Cancer Res 2000;6:2702-6.
  37. Rojas A, Liu G, Coleman I, Nelson PS, Zhang M, Dash R, et al. IL-6 promotes prostate tumorigenesis and progression through autocrine cross-activation of IGF-IR. Oncogene 2011;30:2345-55.
  38. Lo HW, Hsu SC, Xia W, Cao X, Shih JY, Wei Y, et al. Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer Res 2007;67:9066-76.
  39. Mathews LA, Hurt EM, Zhang X, Farrar WL. Epigenetic regulation of CpG promoter methylation in invasive prostate cancer cells. Mol Cancer 2010;9:267.
  40. Xu L, Chen S, Bergan RC. MAPKAPK2 and HSP27 are downstream effectors of p38 MAP kinase-mediated matrix metalloproteinase type 2 activation and cell invasion in human prostate cancer. Oncogene 2006;25:2987-98.
  41. Di K, Wong YC, Wang X. Id-1 promotes TGF-beta1-induced cell motility through HSP27 activation and disassembly of adherens junc- tion in prostate epithelial cells. Exp Cell Res 2007;313:3983-99.
  42. Parra E, Ferreira J, Saenz L. Inhibition of Egr-1 by siRNA in prostate carcinoma cell lines is associated with decreased expression of AP-1 and NF-kappaB. Int J Mol Med 2011;28:847-53.
  43. Vetter G, Le Bechec A, Muller J, Muller A, Moes M, Yatskou M, et al. Time-resolved analysis of transcriptional events during SNAI1-trig- gered epithelial to mesenchymal transition. Biochem Biophys Res Commun 2009;385:485-91.