title: Mutations in the mitochondrial genome confer resistance of cancer cells to anticancer drugs.
abstract: The majority of cancer cells harbor homoplasmic somatic mutations in the mitochondrial genome. We show here that mutations in mitochondrial DNA (mtDNA) are responsible for anticancer drug tolerance. We constructed several trans-mitochondrial hybrids (cybrids) with mtDNA derived from human pancreas cancer cell lines CFPAC-1 and CAPAN-2 as well as from healthy individuals. These cybrids contained the different mitochondrial genomes with the common nuclear background. We compared the mutant and wild-type cybrids for resistance against an apoptosis-inducing reagent and anticancer drugs by exposing the cybrids to staurosporine, 5-fluorouracil, and cisplatin in vitro, and found that all mutant cybrids were more resistant to the apoptosis-inducing and anticancer drugs than wild-type cybrids. Next, we transplanted mutant and wild-type cybrids into nude mice to generate tumors. Tumors derived from mutant cybrids were more resistant than those from wild-type cybrids in suppressing tumor growth and inducing massive apoptosis when 5-fluorouracil and cisplatin were administered. To confirm the tolerance of mutant cybrids to anticancer drugs, we transplanted a mixture of mutant and wild-type cybrids at a 1:1 ratio into nude mice and examined the effect by the drugs on the drift of the ratio of mutant and wild-type mtDNA. The mutant mtDNA showed better survival, indicating that mutant cybrids were more resistant to the anticancer drugs. Thus, we propose that mutations in the mitochondrial genome are potential targets for prognosis in the administration of anticancer drugs to cancer patients.
authors: Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate of School of Medicine, Nippon Medical School, Kawasaki, Japan.
authors: Satoshi
authors: S
authors: Mizutani
authors: Yasuyuki
authors: Y
authors: Miyato
authors: Yujiro
authors: Y
authors: Shidara
authors: Sadamitsu
authors: S
authors: Asoh
authors: Akira
authors: A
authors: Tokunaga
authors: Takashi
authors: T
authors: Tajiri
authors: Shigeo
authors: S
authors: Ohta
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle; D002467:Cell Nucleus; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D054629:Genome, Mitochondrial; D006822:Hybrid Cells; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010101:Oxygen Consumption; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019311:Staurosporine; D002945:Cisplatin; D005472:Fluorouracil