HSP60 IS A NOVEL TARGET IN LETHAL PROSTATE CANCER
Authors: O'Malley Jordan , Donnelly Cullan , Inigo Joseph , Kumar Rahul , Chandra Dhyan 
Published: June 2021

Currently, various therapeutic agents exist in the clinic to treat aggressive prostate cancer (PCa) by modulating androgen receptor (AR) activity, which is one of the main drivers of prostate cancer. However, resistance to these agents nearly always occurs and results in the production of a more aggressive form of cancer, typically referred to as castrate‐recurrent prostate cancer (CRPC). Patients within a subset of CRPC have tumors that undergo neuroendocrine (NE) transdifferentiation (NE‐CRPC). NE‐CRPC is poorly differentiated, readily metastasizes and is resistant to androgen deprivation therapy (ADT). Therefore, it is essential that alternative therapeutic targets that do not solely rely on AR modulation be better characterized for patients with this advanced disease.

The mitochondrial unfolded protein response (mitoUPR) is responsible for maintaining mitochondrial quality control by preserving the integrity of the mitochondria in response to numerous stressors including hypoxia and chemotherapeutic agents. MitoUPR activation is a hallmark sign of mitochondrial dysfunction. Heat Shock Protein60 (Hsp60) is a mitochondrial chaperone and is a key player of the mitoUPR. Thus, we hypothesize that inhibition of Hsp60 renders aggressive NE‐like cells susceptible to stress, thereby alleviating tumorigenicity. We observed that protein expression of Hsp60 was upregulated in tumors derived from NE models such as the transgenic adenocarcinoma of mouse prostate tumor (TRAMP), DKO (pten−/−/rb1−/−) and TKO (rb1−/−/pten−/−/p53−/−) when compared to wild‐type controls. Transcript levels of HSPD1 positively correlated to Gleason Score and are upregulated in patients with NE‐like phenotypes from TCGA. Additionally, Hsp60 expression associated with severe mitochondrial dysfunction in TRAMP tumors. Specifically, mito‐nuclear imbalances and defects in oxidative phosphorylation activity were observed. Lastly, Inhibition of Hsp60 significantly increased sensitivity of NE cells to mitotoxic stressors such as hypoxia and the chemotherapeutic agent cisplatin.

Together, our data indicate that inactivation of Hsp60 sensitizes NE cells to mitotoxic stress and has clinical and therapeutic relevance. Specifically, the use of cisplatin in small cell CRPC has been shown to have minimal effect, yet we determined that inhibition of Hsp60 sensitizes PCa cells to cisplatin. We envision that inactivation of Hsp60 will alleviate tumor burden by itself, but will also enhance sensitivity of chemo‐resistant PCa cells. Additionally, inhibition of Hsp60 may enhance therapeutic potential of anticancer agents in other types of cancers that overexpress Hsp60 including liver, lung and colon cancers. Thus, Hsp60 is a novel target in prostate cancers with NE‐like differentiation.

Support or Funding Information

This work was supported in part by the National Cancer Institute of the National Institutes of Health under Award no. R01CA160685

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.