Mitochondrial Mutagenesis and Oxidative Stress in Human Prostate Cancer

Abstract

Prostate cancer is the most common cancer diagnosed in men in the United States, but the primary cause and the molecular events leading to prostate carcinogenesis are poorly understood. Using the approach of laser capture microdissection, we revealed extensive somatic mitochondrial DNA (mtDNA) mutations in prostatic neoplastic lesions. Inspection of the lesion associated mutations not only provided new insights into the genetics of prostate cancer, but also revealed new patterns of mtDNA mutation in prostate carcinogenesis. Further analysis on a high frequency of multiple mutational events observed in the same neoplastic lesion revealed an unusually rapid process in mitochondrial mutagenesis, suggesting a new process of mitochondrial hyper-mutagenesis in cancer cells, likely mediated by cellular oxidative stress. Thus, active mitochondrial mutagenesis in prostate cancer suggests a prominent role of increased cellular oxidative stress in neoplastic transformation and the increased susceptibility of neoplastic cells to oxidative damage.

Mitochondrial Haplogroups and Polymorphisms Reveal No Association with Sporadic Prostate Cancer in a Southern European Population

“…The T16311C variant was found at higher frequency in patients with T-stage B (also known as stage II), which includes cancers that have not spread outside the prostate (local cancer) [43], [44]. This polymorphism was previously described by Chen et al [45] as a mtDNA mutation detected in the D-loop region in neoplastic lesions dissected from 16 prostatectomy specimens, but no information about clinical features were provided; it has also been found to be significantly associated with human colorectal cancer [46].…”

Mitochondrial DNA mutations in human neoplasia

“…So far, germline and somatic mtDNA mutations have been proven to contribute to prostate cancer (Petros et al 2005). Chen and Kadlubar (2004) revealed extensive somatic mtDNA mutations in prostatic lesions and described specific patterns of mtDNA mutation in prostate carcinogenesis.…”

Selective apoptosis induction by the cancer chemopreventive agent N-(4-hydroxyphenyl)retinamide is achieved by modulating mitochondrial bioenergetics in premalignant and malignant human prostate epithelial cells

“…Despite the routine use of diagnostic indicators for prostate cancer development (e.g., prostate-specific antigen screening), a high cure rate for localized disease, and an increased understanding of prostate cancer biology, most men who develop metastatic prostate cancer will succumb to this disease. Thus, it is clear that effective prostate cancer prevention strategies would spare many men the burden of diagnosis and treatment [1, 2]. …”