mtDNA mutations increase tumorigenicity in prostate cancer

Abstract

Mutations in the mtDNA have been found to fulfill all of the criteria expected for pathogenic mutations causing prostate cancer. Focusing on the cytochrome oxidase subunit I (COI) gene, we found that 11-12% of all prostate cancer patients harbored COI mutations that altered conserved amino acids (mean conservation index ‫؍‬ 83%), whereas <2% of no-cancer controls and 7.8% of the general population had COI mutations, the latter altering less conserved amino acids (conservation index ‫؍‬ 71%). Four conserved prostate cancer COI mutations were found in multiple independent patients on different mtDNA backgrounds. Three other tumors contained heteroplasmic COI mutations, one of which created a stop codon. This latter tumor also contained a germ-line ATP6 mutation. Thus, both germ-line and somatic mtDNA mutations contribute to prostate cancer. Many tumors have been found to produce increased reactive oxygen species (ROS), and mtDNA mutations that inhibit oxidative phosphorylation can increase ROS production and thus contribute to tumorigenicity. To determine whether mutant tumors had increased ROS and tumor growth rates, we introduced the pathogenic mtDNA ATP6 T8993G mutation into the PC3 prostate cancer cell line through cybrid transfer and tested for tumor growth in nude mice. The resulting mutant (T8993G) cybrids were found to generate tumors that were 7 times larger than the wild-type (T8993T) cybrids, whereas the wild-type cybrids barely grew in the mice. The mutant tumors also generated significantly more ROS. Therefore, mtDNA mutations do play an important role in the etiology of prostate cancer.cybrid ͉ oxidative phosphorylation ͉ inherited predisposition

Regulation of mitochondrial DNA content and cancer

“…Additionally, since the inheritance of mitochondrial haplotype U is associated with approximately 2 -fold increased risk of prostate cancer and 2.5-fold increased risk of renal cancer in white North America individuals (Booker et al, 2006), mtDNA definitely affects initiation of cancer. Growth advantage of the cancer cells with specific mutant mtDNA were also demonstrated in vivo mouse model system using cybrid (transmitochondrial hybrid) cells (Petros et al, 2005;Shidara et al, 2005), indicating that specific mutations of mtDNA give advantage of survival to cancer cells. However, Coller et al (Coller et al, 2001) showed that cancer progenitor cells already achieve homoplasmy through stochastic redistribution of the mitochondrial mutation and claimed that replicative advantage of point mutant mtDNA and selective expansion of cancer cells with specific mutant mtDNA are not always necessary to explain homoplasmy of mutant mtDNA in cancer.…”

Mitochondria as therapeutic targets for cancer chemotherapy

“…Some polymorphisms in mitochondrial DNA influence the susceptibility to breast (Canter et al, 2005) and prostate cancer (Petros et al, 2005). Mitochondrial DNA transversion mutations are associated with familial medullary thyroid carcinoma (AbuAmero et al, 2005).…”

Mitochondrial DNA repair in aging and disease

“…A known pathogenic mtDNA mutation in ATP6 was introduced into PC3 cells, a prostate cancer cell line via cybrid transfer. Injection of the resulting ATP6 mutant cybrids into nude mice resulted in the generation of tumors that were seven times larger than those generated from wild type cybrids (122). In addition, the ATP6 mutant cybrid tumors generated significantly more ROS than their wild type counterparts.…”