Cytochrome c-deficiency Confers Apoptosome and Mitochondrial Dysfunction in African-American Men with Prostate Cancer

Although African-American (AA) prostate cancer (PCa) patients tend to develop greater therapeutic resistance and faster PCa recurrence compared to Caucasian-American men, the molecular mechanisms of this racial PCa disparity remain undefined. In this study, we provide the first comprehensive evidence that cytochrome c (CC) deficiency in AA primary tumors and cancer cells abrogates apoptosome-mediated caspase activation and contributes to mitochondrial dysfunction, thereby promoting therapeutic resistance and PCa aggressiveness in AA men. In AA PCa cells, decreased nuclear accumulation of Nrf1 and its subsequent loss of binding to the CC promoter mediated CC deficiency. Activation of c-Myc and NF-κB or inhibition of AKT prevented nuclear translocation of Nrf1. Genetic and pharmacological inhibition of c-Myc and NF-κB or activation of AKT promoted Nrf1 binding to CC promoter, CC expression, caspase activation, and cell death. The lack of p-Drp1S616 in AA PCa cells contributed to defective CC release and increased resistance to apoptosis, indicating that restoration of CC alone may be insufficient to induce effective apoptosis. CC-deficiency promoted acquisition of glycolytic phenotypes and mitochondrial dysfunction, whereas CC restoration via inhibition of c-Myc and NF-κB or activation of AKT attenuated glycolysis in AA PCa cells. Inhibition of c-Myc and NF-κB enhanced the efficacy of docetaxel in tumor xenografts. Therefore, restoring CC may overcome therapeutic resistance and PCa aggressiveness in AA men. Overall, this study provides the first comprehensive experimental, mechanistic, and clinical evidence for apoptosome and mitochondrial dysfunction in PCa racial disparity.

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