Targeting the mitochondria for the treatment of MLH1-deficient disease
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The DNA Mismatch repair (MMR) pathway is responsible for the repair of base-base mismatches and insertion/deletion loops that arise during DNA replication. MMR deficiency is currently estimated to be present in 15-17% of colorectal cancer cases and 30% of endometrial cancers. MLH1 is one of the key proteins involved in the MMR pathway. MMR deficient tumours are often resistant to standard chemotherapies, therefore there is a critical need to identify new therapeutic strategies to treat MMR deficient disease. This study demonstrates that MLH1 deficient tumours are synthetically lethal with the mitochondrial-targeted agent Parthenolide which is known to induce reactive oxygen species (ROS) as one of its main mechanisms of action. Upon functional analysis, I show for the first time that loss of MLH1 is associated with deregulated mitochondrial function evidenced by a reduction in complex I expression and activity, reduced basal oxygen consumption rate and reduced spare respiratory capacity. This mitochondrial phenotype in the MLH1-deficient cell lines is accompanied by a reduction in mitochondrial biogenesis as evidenced by down regulation of pgc1β and decreased mitochondrial copy number. Furthermore, MLH1-deficient cancer cells have a decreased antioxidant defence capacity with reduced expression of the antioxidant genes NRF1, NRF2, Catalase, Glutathione peroxidase and SOD1 as well as increased ROS production when treated with Parthenolide. I further demonstrate that both MSH2- and MSH6-deficient cell lines also display deficiencies in complex I compared to their MMR-proficient counterparts. Taken together, the results of this study show a novel role for MLH1 in mitochondrial function and biogenesis. The MMR proteins MSH2 and MSH6 are also likely to have a role in the mitochondria. My results suggest that targeting the mitochondria may be a potential therapeutic strategy for the treatment of MMR and specifically MLH1 deficient disease.
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