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Heat Shock Protein 27 Confers Resistance to Androgen Ablation and Chemotherapy in Prostate Cancer Cells Through Eif4e

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Heat Shock Protein 27 Confers Resistance to Androgen Ablation and Chemotherapy in Prostate Cancer Cells Through Eif4e Oncogene (2010) 29, 1883–1896 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 $32.00 www.nature.com/onc ORIGINAL ARTICLE Heat shock protein 27 confers resistance to androgen ablation and chemotherapy in prostate cancer cells through eIF4E C Andrieu1,2,6, D Taieb1,2,6, V Baylot1,2, S Ettinger3, P Soubeyran1,2, A De-Thonel4, C Nelson3, C Garrido4,ASo3, L Fazli3, F Bladou5, M Gleave3, JL Iovanna1,2 and P Rocchi1,2 1INSERM, U624 ‘Stress Cellulaire’, Marseille, France; 2Aix-Marseille Universite´, Campus de Luminy, Marseille, France; 3The Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada; 4INSERM U866, Faculte´ de Me´decine, Dijon, France and 5Service d’Urologie de l’Hoˆpital Sainte-Marguerite, Marseille, France One strategy to improve therapies in advanced prostate Oncogene (2010) 29, 1883–1896; doi:10.1038/onc.2009.479; cancer (PC) involves targeting genes that are activated by published online 18 January 2010 androgen withdrawal to delay the emergence of the androgen-independent (AI) phenotype. Heat shock protein Keywords: prostate cancer; androgen independence; 27 (Hsp27) expression becomes highly upregulated in PC heat shock protein 27; eukaryotic translational initiation cells after androgen withdrawal or chemotherapy, in which factor; ubiquitination it functions as a cytoprotective chaperone to confer broad- spectrum treatment resistance. The purpose of this study is to elucidate anti-apoptotic pathways regulated by Hsp27 that are activated during PC progression. Using Introduction two-hybrid experiment, we found that Hsp27 was having a major role in the protein translational initiation process. Prostate cancer (PC) is one of the most common Furthermore, using complementary DNA (cDNA) micro- malignancies in industrialized countries, and the second array analysis, 4E binding protein 1 was identified as leading cause of cancer-related death in the United being proportionately and highly regulated by Hsp27. States. Although patients with localized disease may be These data led us to analyze the protein synthesis treated with surgery or radiation, androgen ablation is initiation pathway, which is a prerequisite for cell growth usually the initial therapy in patients with advanced or and proliferation. Using northern and western blot metastatic disease. Although most patients initially analysis, we found that Hsp27 downregulation decreased respond well to androgen ablation, their tumors eukaryotic translation initiation factor 4E (eIF4E) ultimately become unresponsive and recur within 2 expression at the protein, but not mRNA, level. The years as castration-refractory prostate cancer (CRPC) cytoprotection afforded by Hsp27 overexpression was (Fusi et al., 2004). In the past, chemotherapy had only a attenuated by eIF4E knockdown using specific eIF4E palliative role for men with PC and failed to produce a short interfering RNA (siRNA). Co-immunoprecipitation survival advantage or any significant measurable disease and co-immunofluorescence confirmed that Hsp27 colo- response. Recently, docetaxel-based regimens have calizes and interacts directly with eIF4E. Hsp27-eIF4E shown improved survival in men with CRPC in two interaction decreases eIF4E ubiquitination and proteaso- large, phase III studies (Petrylak et al., 2004; Tannock mal degradation. By chaperoning eIF4E, Hsp27 seems to et al., 2004). However, the median overall survival was protect the protein synthesis initiation process to enhance prolonged for only B2–3 months, and thus development cell survival during cell stress induced by castration or of novel therapeutic approaches are essential, including chemotherapy. Forced overexpression of eIF4E induces antisense and drug therapies that target relevant signaling resistance to androgen-withdrawal and paclitaxel treat- pathways (Gallagher and Gapstur, 2006). ment in the prostate LNCaP cells in vitro. These findings Expression of heat shock protein 27 (Hsp27) is identify Hsp27 as a modulator of eIF4E and establish a upregulated by hormonal ablation and chemotherapy potential mechanism for the eIF4E-regulated apoptosis and is associated with CRPC (Cornford et al., 2000; after androgen ablation and chemotherapy. Targeting Rocchi et al., 2004b). We recently showed using tissue Hsp27–eIF4E interaction may serve as a therapeutic microarray analysis in 232 specimens from hormone- target in advanced PC. naive and post-hormone-treated cancers that Hsp27 expression is low or absent in untreated PC, but starts Correspondence: Dr P Rocchi, Inserm U624, Head of the Prostate increasing 4 weeks after androgen ablation, to become Cancer Research Project, Parc Scientifique et Technologique de uniformly highly expressed in CRPC (Rocchi et al., Luminy, 163 Avenue de Luminy, Marseille, Provence 13009, France. 2005). Hsp27 is an adenosine triphosphate-independent E-mail: [email protected] molecular chaperone that is highly induced during stress 6These authors contributed equally to this work. Received 9 December 2008; revised 15 November 2009; accepted 19 responses and forms oligomers to interact with a wide November 2009; published online 18 January 2010 variety of client proteins, thus preventing their aggregation. Increased Hsp27 induces androgen withdrawal and chemoresistance C Andrieu et al 1884 It has a central role in cellular signaling, as it is essential We next compared the rate of AI progression in for maintaining the activity of key signaling factors, LNCaP tumors in vivo after combined treatment with including steroid hormone receptors (Miller et al., 2005). castration and chemotherapy (defined by increased The cytoprotective effects of Hsp27 result from its tumor volume and rising PSA after castration) chaperone function, direct interference with caspase in LNCaP-Hsp27 (n ¼ 10) and control-transfected activation, modulation of oxidative stress and regulation (n ¼ 10) tumors. By 1 week after castration, LNCaP- of the cytoskeleton (Liang, 2000; Parcellier et al., 2003). Hsp27 tumors showed rapid tumor growth and rise in As an important regulator of cell survival and treatment PSA, consistent with more rapid AI tumor growth stress at many different points along the apoptotic compared with mock-transfected controls. At the time pathways, Hsp27 is now recognized as an important of killing, tumor volume (Figure 1c) was 4.3-fold higher therapeutic target. Recently, Hsp27 antisense oligodeox- in LNCaP-Hsp27 group (1214±321 mm3) than ynucleotides (ASO) and short interfering RNA (siRNA) in LNCaP-Mock control group (357±39.25 mm3 that target the human translation initiation site were **Pp0.01), and serum PSA (Figure 1d) was 9.2-fold reported to potently inhibit Hsp27 expression in human higher in LNCaP-Hsp27 group (68.5±23.14) compared prostate PC-3 cells with increased caspase-3 cleavage, with LNCaP-Mock control group (7.4±1.8 ng/ml, apoptosis and 87% suppression of cell growth (Rocchi **Pp0.01). Immunostaining performed in LNCaP- et al., 2004b, 2005, 2006). A second-generation ASO Mock and LNCaP-Hsp27 cells treated with paclitaxel targeting Hsp27 (OGX-427) is currently being tested in a 10 nM in serum-free media for 24 h showed signifi- phase I/II clinical trial for prostate, bladder, ovarian, cantly higher Ki67 (Figure 1e) and lower single-strand breast and lung cancers in Canada and the United States DNA (Figure 1f) expression level in LNCaP-Hsp27 (Hotte et al., 2009; http://www.oncogenex.ca/). compared with LNCaP-Mock control cells. Accord- An improved understanding of the mechanisms of ing to previous work published by Garrido and action of Hsp27, and characterization of additional Parcellier (Garrido et al., 2003; Parcellier et al., 2006), putative cell survival proteins, will improve our under- these data imply that increased Hsp27 levels protect standing of apoptotic regulatory pathways and androgen-dependent prostate cancer cells from treat- drug resistance. The objective of this study was to assess ment stress induced by increasing tumor proliferation the effect of Hsp27 overexpression on chemotherapy and decreasing apoptosis, thereby facilitating tumor and androgen withdrawal-induced apoptosis. We progression. chose the LNCaP tumor model that closely mimics androgen-independent (AI) progression in humans Hsp27 expression affects levels of the eIF4E, and its and produces prostate-specific antigen (PSA). LNCaP binding protein, 4E-BP1 tumors are androgen dependent when injected into male To explore the molecular mechanisms of apoptotic immunodeficient mice, and develop non-androgen- resistance associated with Hsp27 overexpression in regulated PSA gene expression after castration, LNCaP cells, we found using western blot that Hsp27 as a surrogate end point of AI progression (Gleave inhibition by OGX-427 could inhibit several proteins et al., 1992). As part of our ongoing analyses for involved in AI progression, such as androgen receptor, identifying key pathways mediating AI progression, we heat shock proteins 70 and 90 (Hsp70 and Hsp90) and overexpressed Hsp27 for gain-of-function analyses and heat shock factor 1, without affecting their mRNA level. used OGX-427 for loss-of-function analyses to under- On the other hand, we performed Hsp27 two-hybrid stand how Hsp27 imposes its cytoprotective effect experiments to find Hsp27 protein partners and found on cells after androgen withdrawal and chemotherapy that Hsp27 was having a major role in the protein in PCs. translational initiation process (not shown). Further- more, we also followed an unbiased approach using expression profiling
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