Format

Send to

Choose Destination
Cancer Res. 2019 Apr 1;79(7):1353-1368. doi: 10.1158/0008-5472.CAN-18-2383. Epub 2019 Feb 14.

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

Author information

1
Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
2
Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of Health Sciences, Bethesda, Maryland.
3
Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
4
Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
5
Department of Biostatistics, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
6
Pathology Resource Network, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
7
Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
8
Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York. dhyan.chandra@roswellpark.org.

Abstract

Although African-American (AA) patients with prostate cancer tend to develop greater therapeutic resistance and faster prostate cancer recurrence compared with Caucasian-American (CA) men, the molecular mechanisms of this racial prostate cancer disparity remain undefined. In this study, we provide the first comprehensive evidence that cytochrome c deficiency in AA primary tumors and cancer cells abrogates apoptosome-mediated caspase activation and contributes to mitochondrial dysfunction, thereby promoting therapeutic resistance and prostate cancer aggressiveness in AA men. In AA prostate cancer cells, decreased nuclear accumulation of nuclear respiration factor 1 (Nrf1) and its subsequent loss of binding to the cytochrome c promoter mediated cytochrome c deficiency. The activation of cellular Myc (c-Myc) and NF-κB or inhibition of AKT prevented nuclear translocation of Nrf1. Genetic and pharmacologic inhibition of c-Myc and NF-κB or activation of AKT promoted Nrf1 binding to cytochrome c promoter, cytochrome c expression, caspase activation, and cell death. The lack of p-Drp1S616 in AA prostate cancer cells contributed to defective cytochrome c release and increased resistance to apoptosis, indicating that restoration of cytochrome c alone may be insufficient to induce effective apoptosis. Cytochrome c deficiency promoted the acquisition of glycolytic phenotypes and mitochondrial dysfunction, whereas cytochrome c restoration via inhibition of c-Myc and NF-κB or activation of AKT attenuated glycolysis in AA prostate cancer cells. Inhibition of c-Myc and NF-κB enhanced the efficacy of docetaxel in tumor xenografts. Therefore, restoring cytochrome c may overcome therapeutic resistance and prostate cancer aggressiveness in AA men. Overall, this study provides the first comprehensive experimental, mechanistic, and clinical evidence for apoptosome and mitochondrial dysfunction in prostate cancer racial disparity. SIGNIFICANCE: Mechanistic insights on prostate cancer health disparity among American men provide novel approaches to restore mitochondrial function, which can address therapeutic resistance and aggressiveness in African-American men with prostate cancer.

PMID:
30765600
PMCID:
PMC6445777
[Available on 2020-04-01]
DOI:
10.1158/0008-5472.CAN-18-2383

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center