Investigating Mitochondrial and Apoptosome Dysfunction
Higher prostate cancer diagnosis and related mortality are commonly associated with African American (AA) men compared to Caucasian American (CA) men. We provide evidence that reduced level of mitochondrial DNA and reduced expression of cytochrome c contribute to mitochondrial and apoptosome dysfunction in AA patients with prostate cancer.
- Cytochrome c-deficiency is mediated by abrogation of nuclear respiration factor-1 (Nrf1) nuclear accumulation and its binding to the cytochrome c promoter in prostate cancer.
- Mechanistic analysis defines that hyper-activation of c-Myc and NF-κB prevents Nrf1 nuclear translocation leading to cytochrome c-deficiency in cancer cells.
- Inhibition of c-Myc, NF-κB, and glycolysis promotes cytochrome c expression, caspase activation, and apoptosis in prostate cancer and tumor cells.
Thus, restoring mitochondrial apoptosis in AA prostate cancer cells will reduce apparent racial disparity among American men with prostate cancer.
- Kumar R, et al. Cytochrome c-Deficiency Confers Apoptosome and Mitochondrial Dysfunction in African-American Men with Prostate Cancer. Cancer Res. 2019 Apr 1;79(7):1353-1368. doi: 10.1158/0008-5472.CAN-18-2383. Epub 2019 Feb 14. PMID: 30765600; PMCID: PMC6445777.
- Chaudhary AK, O'Malley J, Kumar S, Inigo JR, Kumar R, Yadav N, Chandra D. Mitochondrial dysfunction and prostate cancer racial disparities among American men. Front Biosci (Schol Ed). 2017 Jan 1;9(1):154-164. doi: 10.2741/s479. PMID: 27814581.
- Koochekpour S, Marlowe T, Singh KK, Attwood K, Chandra D. Reduced mitochondrial DNA content associates with poor prognosis of prostate cancer in African American men. PLoS One. 2013 Sep 23;8(9):e74688. PMID: 24086362.