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Heat shock protein 27 confers resistance to androgen ablation and chemotherapy in prostate cancer cells through eIF4E

Oncogene volume 29, pages 1883–1896 (2010)Cite this article

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Abstract

One strategy to improve therapies in advanced prostate cancer (PC) involves targeting genes that are activated by androgen withdrawal to delay the emergence of the androgen-independent (AI) phenotype. Heat shock protein 27 (Hsp27) expression becomes highly upregulated in PC cells after androgen withdrawal or chemotherapy, in which 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 two-hybrid experiment, we found that Hsp27 was having a major role in the protein translational initiation process. Furthermore, using complementary DNA (cDNA) microarray analysis, 4E binding protein 1 was identified as being proportionately and highly regulated by Hsp27. These data led us to analyze the protein synthesis initiation pathway, which is a prerequisite for cell growth and proliferation. Using northern and western blot analysis, we found that Hsp27 downregulation decreased eukaryotic translation initiation factor 4E (eIF4E) expression at the protein, but not mRNA, level. The cytoprotection afforded by Hsp27 overexpression was attenuated by eIF4E knockdown using specific eIF4E short interfering RNA (siRNA). Co-immunoprecipitation and co-immunofluorescence confirmed that Hsp27 colocalizes and interacts directly with eIF4E. Hsp27-eIF4E interaction decreases eIF4E ubiquitination and proteasomal degradation. By chaperoning eIF4E, Hsp27 seems to protect the protein synthesis initiation process to enhance cell survival during cell stress induced by castration or chemotherapy. Forced overexpression of eIF4E induces resistance to androgen-withdrawal and paclitaxel treatment in the prostate LNCaP cells in vitro. These findings identify Hsp27 as a modulator of eIF4E and establish a potential mechanism for the eIF4E-regulated apoptosis after androgen ablation and chemotherapy. Targeting Hsp27–eIF4E interaction may serve as a therapeutic target in advanced PC.

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Acknowledgements

We thank Dr Valentina Evdokimova (British Columbia Cancer Agency, Canada) for her helpful advice on eIF4E experiments. We thank Dr Takayuki Murata (McGill University, Canada) for providing the pcDNA3.1 FLAG-tagged eIF4E vectors. We thank Virginia Yago and Paul Jugpal (Prostate Centre, Canada) for their excellent technical assistance in animal and laboratory experimentation. We thank Dr Jonathan Nowak (Inserm U624, France) for his excellent help in confocal microscopy. This work was supported from grants by l’Institut National de la Santé et de la Recherche Médicale (INSERM), l’Association pour la Recherche sur le Cancer (ARC) and l’Association pour la Recherche sur les Tumeurs de la Prostate (ARTP).

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  1. C Andrieu and D Taieb: These authors contributed equally to this work.

Authors and Affiliations

  1. INSERM, U624 ‘Stress Cellulaire’, Marseille, France

    C Andrieu, D Taieb, V Baylot, P Soubeyran, J L Iovanna & P Rocchi

  2. Aix-Marseille Université, Campus de Luminy, Marseille, France

    C Andrieu, D Taieb, V Baylot, P Soubeyran, J L Iovanna & P Rocchi

  3. The Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, Canada

    S Ettinger, C Nelson, A So, L Fazli & M Gleave

  4. INSERM U866, Faculté de Médecine, Dijon, France

    A De-Thonel & C Garrido

  5. Service d’Urologie de l’Hôpital Sainte-Marguerite, Marseille, France

    F Bladou

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Correspondence to P Rocchi.

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Andrieu, C., Taieb, D., Baylot, V. et al. Heat shock protein 27 confers resistance to androgen ablation and chemotherapy in prostate cancer cells through eIF4E. Oncogene 29, 1883–1896 (2010). https://doi.org/10.1038/onc.2009.479

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