Oncotarget

Research Papers:

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

Boyun Kim, Je Won Jung, Jaeyoung Jung, Youngjin Han, Dong Hoon Suh, Hee Seung Kim, Danny N. Dhanasekaran and Yong Sang Song _

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Oncotarget. 2017; 8:60299-60311. https://doi.org/10.18632/oncotarget.19140

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Abstract

Boyun Kim1,2, Je Won Jung3, Jaeyoung Jung1,4, Youngjin Han1,4, Dong Hoon Suh5, Hee Seung Kim7, Danny N. Dhanasekaran6 and Yong Sang Song1,4,7

1Cancer Research Institute, College of Medicine, Seoul National University, Seoul 03080, Korea

2Nano System Institute, Seoul National University, Seoul 08826, Korea

3Research Institute of Agriculture and Life Sciences, Seoul National University, Seoul 08826, Korea

4WCU Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul 08826, Korea

5Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam 13620, Korea

6Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73012, United States of America

7Department of Obstetrics and Gynecology, College of Medicine, Seoul National University, Seoul 03080, Korea

Correspondence to:

Yong Sang Song, email: [email protected]

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.


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