title: Mitochondrial Superoxide Dismutase Has a Protumorigenic Role in Ovarian Clear Cell Carcinoma.
abstract: Epithelial ovarian cancer (EOC) is the fourth leading cause of death due to cancer in women and comprises distinct histologic subtypes, which vary widely in their genetic profiles and tissues of origin. It is therefore imperative to understand the etiology of these distinct diseases. Ovarian clear cell carcinoma (OCCC), a very aggressive subtype, comprises >10% of EOCs. In the present study, we show that mitochondrial superoxide dismutase (Sod2) is highly expressed in OCCC compared with other EOC subtypes. Sod2 is an antioxidant enzyme that converts highly reactive superoxide (O2 (•-)) to hydrogen peroxide (H2O2) and oxygen (O2), and our data demonstrate that Sod2 is protumorigenic and prometastatic in OCCC. Inhibiting Sod2 expression reduces OCCC ES-2 cell tumor growth and metastasis in a chorioallantoic membrane (CAM) model. Similarly, cell proliferation, migration, spheroid attachment and outgrowth on collagen, and Akt phosphorylation are significantly decreased with reduced expression of Sod2. Mechanistically, we show that Sod2 has a dual function in supporting OCCC tumorigenicity and metastatic spread. First, Sod2 maintains highly functional mitochondria, by scavenging O2 (•-), to support the high metabolic activity of OCCC. Second, Sod2 alters the steady-state ROS balance to drive H2O2-mediated migration. While this higher steady-state H2O2 drives prometastatic behavior, it also presents a doubled-edged sword for OCCC, as it pushed the intracellular H2O2 threshold to enable more rapid killing by exogenous sources of H2O2. Understanding the complex interaction of antioxidants and ROS may provide novel therapeutic strategies to pursue for the treatment of this histologic EOC subtype.
authors.affiliation: Nanobioscience Constellation, Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, State University of New York, Albany, New York.
authors.forename: L P Madhubhani P
authors.initials: LP
authors.lastname: Hemachandra
authors.affiliation: Nanobioscience Constellation, Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, State University of New York, Albany, New York. Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania.
authors.forename: Dong-Hui
authors.initials: DH
authors.lastname: Shin
authors.affiliation: Nanobioscience Constellation, Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, State University of New York, Albany, New York.
authors.forename: Usawadee
authors.initials: U
authors.lastname: Dier
authors.affiliation: Department of Chemistry, Stony Brook University, State University of New York, Stony Brook, New York.
authors.forename: James N
authors.initials: JN
authors.lastname: Iuliano
authors.affiliation: Nanobioscience Constellation, Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, State University of New York, Albany, New York.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Engelberth
authors.affiliation: Nanobioscience Constellation, Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, State University of New York, Albany, New York.
authors.forename: Larissa M
authors.initials: LM
authors.lastname: Uusitalo
authors.affiliation: Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Murphy
authors.affiliation: Nanobioscience Constellation, Colleges of Nanoscale Science and Engineering, SUNY Polytechnic Institute, State University of New York, Albany, New York. Department of Pharmacology, Penn State College of Medicine, Hershey, Pennsylvania. nhempel@hmc.psu.edu.
authors.forename: Nadine
authors.initials: N
authors.lastname: Hempel
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000201:enzymology* / Q000473:pathology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D015151:Immunoblotting; D009361:Neoplasm Invasiveness / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*; D000099156:Superoxide Dismutase 2
chemical_list: D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2