PGC1? induced by reactive oxygen species contributes to chemoresistance of ovarian cancer cells.

ABSTRACT: Malignant cells are subjected to high levels of oxidative stress that arise from the increased production of reactive oxygen species (ROS) due to their altered metabolism. They activate antioxidant mechanisms to relieve the oxidative stress, and thereby acquire resistance to chemotherapeutic agents. In the present study, we found that PGC1?, a key molecule that both increases mitochondrial biogenesis and activates antioxidant enzymes, enhances chemoresistance in response to ROS generated by exposure of cells to ovarian sphere-forming culture conditions. Cells in the cultured spheres exhibited stem cell-like characteristics, and maintained higher ROS levels than their parent cells. Intriguingly, scavenging ROS diminished the aldehyde dehydrogenase (ALDH)-positive cell population, and inhibited proliferation of the spheres. ROS production triggered PGC1? expression, which in turn caused changes to mitochondrial biogenesis and activity within the spheres. The drug-resistant phenotype was observed in both spheres and PGC1?-overexpressing parent cells, and conversely, PGC1? knockdown sensitized the spheres to cisplatin treatment. Similarly, floating malignant cells derived from patient ascitic fluid included an ALDH-positive population and exhibited the tendency of a positive correlation between expressions of multidrug resistance protein 1 (MDR1) and PGC1?. The present study suggests that ROS-induced PGC1? mediates chemoresistance, and represents a novel therapeutic target to overcome chemoresistance in ovarian cancer.

SUBMITTER: Kim B 

PROVIDER: S-EPMC5601140 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature