Targeting the mitochondria for the treatment of MLH1-deficient disease
Abstract
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.
Authors
Rashid, SukainaCollections
- Theses [4116]