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.

This article is referred to by:

Mutant mitochondria and cancer cell metastasis: Quest for a mechanism