PGC1α induced by reactive oxygen species contributes to chemoresistance of ovarian cancer cells

Abstract

// Boyun Kim 1, 2 , Je Won Jung 3 , Jaeyoung Jung 1, 4 , Youngjin Han 1, 4 , Dong Hoon Suh 5 , Hee Seung Kim 7 , Danny N. Dhanasekaran 6 and Yong Sang Song 1, 4, 7 1 Cancer Research Institute, College of Medicine, Seoul National University, Seoul 03080, Korea 2 Nano System Institute, Seoul National University, Seoul 08826, Korea 3 Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul 08826, Korea 4 WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul 08826, Korea 5 Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam 13620, Korea 6 Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73012, United States of America 7 Department of Obstetrics and Gynecology, College of Medicine, Seoul National University, Seoul 03080, Korea Correspondence to: Yong Sang Song, email: yssong@snu.ac.kr Keywords: ovarian cancer, ROS, PGC1α, chemoresistance, mitochondria Received: November 16, 2016     Accepted: June 10, 2017     Published: July 10, 2017 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 PGC1α, 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 PGC1α expression, which in turn caused changes to mitochondrial biogenesis and activity within the spheres. The drug-resistant phenotype was observed in both spheres and PGC1α-overexpressing parent cells, and conversely, PGC1α 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 PGC1α. The present study suggests that ROS-induced PGC1α mediates chemoresistance, and represents a novel therapeutic target to overcome chemoresistance in ovarian cancer.