Cancer cell mitochondria confer apoptosis resistance and promote metastasis

 Abstract

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 mutation in tRNA Leu (CUN) gene known to be involved in pathogenesis of
mitochondrial diseases. We generated a mutant cybrid (cytoplasmic hybrid) by
repopulating the recipient ρ0 (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, 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 metastatis
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.

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Pages
1378 - 1385
doi
10.4161/cbt.8.14.8751
Type
Research Paper
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Cancer cell mitochondria confer apoptosis resistance and promote metastasis