Cancer cell mitochondria confer apoptosis resistance and promote metastasis.
Mutations in mtDNA are found in most cancers. In this study, we studied the role of cancer cell mutant mtDNA in tumorigenesis. We sequenced the entire mitochondrial genome of three different breast cancer cell lines and found that all three, MCF7, MDA-MB-231 and MDA-MB-435, contained mutations in mtDNA. MDA-MB-435 cells contained a mutation in the tRNA(Leu(CUN)) gene known to be involved in pathogenesis of mitochondrial diseases. We generated a mutant cybrid (cytoplasmic hybrid) by repopulating the recipient rho(0) (completely devoid of mtDNA) cells with donor mtDNA derived from an enucleated MDA-MB-435 breast cancer cell line. An isogenic wild-type cybrid was produced by transfer of normal mtDNA from a healthy donor. When compared to the wild type, we found that mutant mtDNA increases mitochondrial membrane potential. However, this increase in mitochondrial membrane potential was not associated with increase in reactive oxygen species (ROS) production. MtDNA mutations conferred resistance to apoptosis triggered by etoposide. Our study also revealed that mutations in mtDNA increase metastatic potential. Using a tail-vein model of metastasis in a mouse model, we show that the mutant cybrid metastatizes to the lungs and forms macrometastic foci. Additionally we found that mutations in mtDNA constitutively activate the PI3/Akt pathway that contributes to increased metastatis. Together our study demonstrates that mutant mtDNA promotes apoptotic resistance and metastasis in a mouse model.
Kulawiec
Mariola
M
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Owens
Kjerstin M
KM
Singh
Keshav K
KK
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000556:secondary*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D006801:Humans; D006822:Hybrid Cells / Q000473:pathology / Q000637:transplantation; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology / Q000556:secondary; D053078:Membrane Potential, Mitochondrial / Q000235:genetics / Q000502:physiology; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000502:physiology*; D020125:Mutation, Missense; D009362:Neoplasm Metastasis / Q000235:genetics*; D009363:Neoplasm Proteins / Q000502:physiology; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D017422:Sequence Analysis, DNA
D004272:DNA, Mitochondrial; D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species; D019869:Phosphatidylinositol 3-Kinases; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt