A mitochondrial unfolded protein response inhibitor suppresses prostate cancer growth in mice via HSP60
Rahul Kumar, Ajay K. Chaudhary, Jordan Woytash, Joseph R. Inigo, Abhiram A. Gokhale, Wiam Bshara, Kristopher Attwood, Jianmin Wang, Joseph A. Spernyak, Eva Rath, Neelu Yadav, Dirk Haller, David W. Goodrich, Dean G. Tang, Dhyan Chandra
Rahul Kumar, Ajay K. Chaudhary, Jordan Woytash, Joseph R. Inigo, Abhiram A. Gokhale, Wiam Bshara, Kristopher Attwood, Jianmin Wang, Joseph A. Spernyak, Eva Rath, Neelu Yadav, Dirk Haller, David W. Goodrich, Dean G. Tang, Dhyan Chandra
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Research Article Cell biology Oncology

A mitochondrial unfolded protein response inhibitor suppresses prostate cancer growth in mice via HSP60

Abstract

Mitochondrial proteostasis, regulated by the mitochondrial unfolded protein response (UPRmt), is crucial for maintenance of cellular functions and survival. Elevated oxidative and proteotoxic stress in mitochondria must be attenuated by the activation of a ubiquitous UPRmt to promote prostate cancer (PCa) growth. Here we show that the 2 key components of the UPRmt, heat shock protein 60 (HSP60, a mitochondrial chaperonin) and caseinolytic protease P (ClpP, a mitochondrial protease), were required for the development of advanced PCa. HSP60 regulated ClpP expression via c-Myc and physically interacted with ClpP to restore mitochondrial functions that promote cancer cell survival. HSP60 maintained the ATP-producing functions of mitochondria, which activated the β-catenin pathway and led to the upregulation of c-Myc. We identified a UPRmt inhibitor that blocked HSP60’s interaction with ClpP and abrogated survival signaling without altering HSP60’s chaperonin function. Disruption of HSP60-ClpP interaction with the UPRmt inhibitor triggered metabolic stress and impeded PCa-promoting signaling. Treatment with the UPRmt inhibitor or genetic ablation of Hsp60 inhibited PCa growth and progression. Together, our findings demonstrate that the HSP60-ClpP–mediated UPRmt is essential for prostate tumorigenesis and the HSP60-ClpP interaction represents a therapeutic vulnerability in PCa.

Authors

Rahul Kumar, Ajay K. Chaudhary, Jordan Woytash, Joseph R. Inigo, Abhiram A. Gokhale, Wiam Bshara, Kristopher Attwood, Jianmin Wang, Joseph A. Spernyak, Eva Rath, Neelu Yadav, Dirk Haller, David W. Goodrich, Dean G. Tang, Dhyan Chandra

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Figure 4

The UPRmt components are upregulated in human PCa.

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The UPRmt components are upregulated in human PCa. (A) Hsp60 transcript ...
(A) Hsp60 transcript reads in prostate tumors compared to matched normal counterparts from TCGA 2015 data set. (B) Hsp10 transcript reads in prostate tumors (PTs) compared to matched normal (MN) counterparts from TCGA 2015 data set. (C) ClpP transcript reads in PTs compared to MN counterparts from TCGA 2015 data set. (D) Correlative analysis between Hsp60 and ClpP transcript reads from TCGA 2015 data set. (E) Correlative analysis between Hsp60 and Hsp10 transcript reads from TCGA 2015 data set. (F) Hsp60 transcript reads in PTs compared to MN counterparts from the MSKCC 2010 data set. (G) Hsp10 transcript reads in PTs compared to MN counterparts from the MSKCC 2010 data set. (H) ClpP transcript reads in PTs compared to MN counterparts from the MSKCC 2010 data set. (I) Representative IHC images from PCa TMA stained with H&E and for HSP60 or ClpP. Scale bars: 500 μm (rows 1 and 3) and 200 μm (rows 2 and 4). (J) Anti-ClpP and -HSP60 IHC images were scored and quantified. (K) Protein expression of HSP60, HSP10, and ClpP in nonmalignant normal prostate cell lines (RWPE1 and HPN-5) and various PCa cell lines. GAPDH serves as a loading control. P values were calculated by 2-tailed Student’s t test (A–H and J).