Hsp60 Regulation of Prostate Cancer Progression

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Mitochondrial protein homeostasis (proteostasis) has been implicated in cancer and is regulated by mitochondrial unfolded protein response (UPRmt). However, it is unknown whether UPRmt promotes tumorigenesis and whether it could be targeted for therapeutic benefit in prostate cancer (PCa). This proposal will define how heat shock protein 60 (HSP60), a key component of UPRmt, promotes aggressive and resistant PCa. Using genetically-engineered triple knockout (TKO: deletion of Pten, Trp53, and Rb1) tumors, we observed that HSP60 is upregulated in aggressive tumors and castration-resistant prostate cancer (CRPC) compared to WT prostatic tissues. TCGA data analysis and our preliminary data using human PCa-specific TMAs demonstrated that HSP60 is upregulated in prostate tumors with higher Gleason Scores. HSP60-silencing induced caspase activation and inhibited cellular proliferation whereas HSP60 overexpression promoted cancer cell survival and proliferation. We provide the first evidence that, genetic deletion of HSP60 in TKO mouse and inhibition of HSP60 oligomerization by introducing HSP60D3G KI during prostate tumorigenesis, reduced tumor burden in vivo. We observed that activating transcription factor 5 (ATF5), specific for HSP60 expression and UPRmt activation, was upregulated with higher Gleason Scores, and ATF5 was translocated to nucleus during stress. Using in silico analysis, we have identified a novel UPRmt inhibitor (referred to as DCEM1), which induced robust apoptosis in PCa cells and blocked tumor growth in vivo. Based on these findings, we hypothesized that HSP60- dependent mitochondrial unfolded protein response promotes cancer cell adaptation during tumor progression and therapeutic resistance in PCa. Identification of UPRmt inhibitor provides alternative treatment option for patients with PCa. We propose the following Specific Aims to test this hypothesis. Aim 1. Define the role of transcription factor ATF5 in activating mitochondrial unfolded protein response. Aim 2: Evaluate whether HSP60 oligomerization maintains functional mitochondria and inhibits apoptosis to develop aggressive PCa. Aim 3. Explore the clinical relevance of HSP60 inhibition using patient-derived xenografts (PDXs) and primary tumor cells. Impact: The findings will provide fundamental understanding on how UPRmt is activated and how persistent mitochondrial stress is attenuated by UPRmt leading to development of aggressive and lethal PCa. Identification of unique UPRmt inhibitor represents a new therapeutic vulnerability in PCa that does not rely on androgen modulation. Therefore, UPRmt inhibition by DCEM1 will have greater therapeutic benefits for patients with androgen-dependent and androgen-independent CRPC.