Mitochondrial associated granulocyte macrophage colony stimulating factor (Magmas) is a novel protein that is located in the inner membrane of mitochondria and is an effective scavenger of reactive oxygen species (ROS) in cellular systems. Ovarian Cancer (OC) is one of the lethal gynaecological cancers that affects about 1 in 79 women in Australia with an estimated 1510 cases diagnosed each year. The cancer is characterised by genomic instability and is directly affected by ROS production in the tumour microenvironment. OC has a recurrence rate of 75% with a five-year survival rate of 30%. Peritoneal metastasis, and chemoresistance associated recurrence is a major factor of mortality in OC. This project investigates the role of Magmas and efficacy of its novel small molecule inhibitor BT#9 in progression, metastasis and chemoresistance of ovarian cancer.
We show that the expression of Magmas increases significantly in high-grade OC compared to benign ovarian tumours. The expression of Magmas was inversely correlated with the expression of 4-Hydroxynonenol (4-HNE) in ovarian tumours indicating the ROS scavenging role of Magmas demonstrated before. In vitro studies on ovarian cancer cell lines have shown that BT#9 inhibits basal respiration, mitochondrial ATP production with a major decrease in mitochondrial functionality. BT#9 treatment also caused decreased cell migration, proliferation and increased cell death via enhancing ROS production.
In vivo oral administration of BT#9 is effective in prolonging survival of mice by reducing tumour burden and preventing dissemination of tumour in the mouse abdominal organs. Mouse experiments also showed that BT#9 treatment makes tumour cells more prone to be targeted by immune system.
Overall, our data suggests that understanding role of Magmas in OC may help us better understand the progression and metastasis in OC. We also hypothesize that Magmas might have a role in chemoresistance/recurrence in OC which is being explored via on going experiments.