Dhyan Chandra, PhD
Professor of Oncology, Department of Pharmacology and Therapeutics, Center for Genetics and Pharmacology, Roswell Park Comprehensive Cancer Center

“Mitochondrial Unfolded Protein Response and Racial Disparities in Prostate Cancer”

Abstract

We study the importance of mitochondrial biology in prostate cancer by focusing on two major research areas. First, we have identified the mitochondrial unfolded protein response (UPRmt) as a new target for prostate cancer treatment and management. We discovered that the two key components of the UPRmt, heat shock protein 60 (HSP60, a mitochondrial chaperonin) and caseinolytic protease (ClpP, a mitochondrial protease) work together and are required for the development of advanced prostate cancer. HSP60 acts as upstream regulator of ClpP expression and HSP60 interacts with ClpP to maintain mitochondrial function. We have discovered a novel UPRmt (referred to as DCEM1) that inhibits HSP60 interactions with ClpP in prostate cancer cells and prostate tumors, leading to the blockade prostate cancer growth and progression in preclinical study. Second, higher prostate cancer diagnosis and related mortality are commonly associated with African-American (AA) compared to Caucasian-American (CA) men. We are the first to define that AA patients with prostate cancer harbor reduced expression of cytochrome c causing apoptosome and mitochondrial dysfunction. We further dissected that apoptosome and mitochondrial dysfunction in AA cells is the one of the key reasons for prostate cancer racial disparities among American men. Thus, restoring mitochondrial apoptosis in AA prostate cancer cells will reduce apparent racial disparity among American men with prostate cancer.