HSP90 Chaperone Proteins and Interactors in Cellular Signal Transduction

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In FY2021, (1) We confirmed that alternatively spliced androgen receptor (lacking ligand binding domain with which Hsp90 interacts) interacts with and remains dependent on Hsp40 and Hsp70 for stability and transcriptional activity. Further, we showed that targeting the Hsp40/Hsp70 chaperone axis is a novel strategy to treat castration-resistant prostate cancer that has become resistant to standard antiandrogen therapy. (2) We identified a multichaperone complex in mitochondria comprised of Trap1, Hsp60 and mitochondrial Hsp70 as a regulator of oxidative phosphorylation and ATP synthase-mediated ATP production. Assembly of the multichaperone complex is sensitive to mitochondrial ATP level. We identified multiple subunits of ATP synthase and numerous electron transport chain components as Trap1 interactors (potential clients), and we demonstrated that Trap1 knockout leads to increased oxidative phosphorylation and a strong preference for glutamine as the primary carbon source for the TCA cycle. (3) We also demonstrated that Hsp70 inhibition blocked both heat-induced and Hsp90 inhibitor-potentiated HSF1 activation and transcriptional activity by causing the destabilization of HSF1. We showed that Hsp70 bound to both HSF1 monomers (inactive) and trimers (active). In FY22 we confirmed in vitro and in vivo activity of Hsp70 inhibitor on castrate resistant prostate, but demonstrated an early and profound effect on mitochondrial protein translation which leads to disruption of electron transport chain (ETC) complex I, with resultant collapse of the ETC. This outcome is phenocopied by a specific inhibitor of complex I. In both cases, disruption of mitochondrial respiration restores sensitivity to enzalutamide. In vitro effects are reproducible in vivo and can be non-invasively imaged with hyperpolarized pyruvate MR spectroscopy (HP-MRSI).