American Association for Cancer Research
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Figure S4 from Regulation of eIF4F Translation Initiation Complex by the Peptidyl Prolyl Isomerase FKBP7 in Taxane-resistant Prostate Cancer

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posted on 2023-03-31, 21:47 authored by Marine F. Garrido, Nicolas J.-P. Martin, Matthieu Bertrand, Catherine Gaudin, Frédéric Commo, Nassif El Kalaany, Nader Al Nakouzi, Ladan Fazli, Elaine Del Nery, Jacques Camonis, Franck Perez, Stéphanie Lerondel, Alain Le Pape, Daniel Compagno, Martin Gleave, Yohann Loriot, Laurent Désaubry, Stéphan Vagner, Karim Fizazi, Anne Chauchereau

Chemoresistant mouse model

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AMMICA

Vasily Ogryzko

Camargo Foundation

Terry Fox Foundation

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ARTICLE ABSTRACT

Targeted therapies that use the signaling pathways involved in prostate cancer are required to overcome chemoresistance and improve treatment outcomes for men. Molecular chaperones play a key role in the regulation of protein homeostasis and are potential targets for overcoming chemoresistance.Experimental Design: We established 4 chemoresistant prostate cancer cell lines and used image-based high-content siRNA functional screening, based on gene-expression signature, to explore mechanisms of chemoresistance and identify new potential targets with potential roles in taxane resistance. The functional role of a new target was assessed by in vitro and in vivo silencing, and mass spectrometry analysis was used to identify its downstream effectors. We identified FKBP7, a prolyl-peptidyl isomerase overexpressed in docetaxel-resistant and in cabazitaxel-resistant prostate cancer cells. This is the first study to characterize the function of human FKBP7 and explore its role in cancer. We discovered that FKBP7 was upregulated in human prostate cancers and its expression correlated with the recurrence observed in patients receiving docetaxel. FKBP7 silencing showed that FKBP7 is required to maintain the growth of chemoresistant cell lines and chemoresistant tumors in mice. Mass spectrometry analysis revealed that FKBP7 interacts with eIF4G, a component of the eIF4F translation initiation complex, to mediate the survival of chemoresistant cells. Using small-molecule inhibitors of eIF4A, the RNA helicase component of eIF4F, we were able to kill docetaxel- and cabazitaxel-resistant cells. Targeting FKBP7 or the eIF4G-containing eIF4F translation initiation complex could be novel therapeutic strategies to eradicate taxane-resistant prostate cancer cells.

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