mtDNA mutations increase tumorigenicity in prostate cancer.
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.
Petros
John A
JA
Department of Urology, Emory University, 1365A Clifton Road, Atlanta, GA 30322, USA.
Baumann
Amanda K
AK
Ruiz-Pesini
Eduardo
E
Amin
Mahul B
MB
Sun
Carrie Qi
CQ
Hall
John
J
Lim
SoDug
S
Issa
Muta M
MM
Flanders
W Dana
WD
Hosseini
Seyed H
SH
Marshall
Fray F
FF
Wallace
Douglas C
DC
D000251:Adenosine Triphosphatases / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D025261:Mitochondrial Proton-Translocating ATPases; D009154:Mutation / Q000502:physiology*; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D021122:Protein Subunits; D017382:Reactive Oxygen Species / Q000378:metabolism
D004272:DNA, Mitochondrial; C501005:MT-ATP6 protein, human; D021122:Protein Subunits; D017382:Reactive Oxygen Species; D003576:Electron Transport Complex IV; D000251:Adenosine Triphosphatases; D025261:Mitochondrial Proton-Translocating ATPases; C501006:mt-Atp6 protein, mouse