Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells.

Autor: Kim YS; Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA., Gupta Vallur P; Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA., Jones VM; Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA., Worley BL; Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA., Shimko S; Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA., Shin DH; Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA., Crawford LC; Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA., Chen CW; Department of Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, Hershey, PA, USA., Aird KM; Department of Cellular and Molecular Physiology, College of Medicine, Pennsylvania State University, Hershey, PA, USA., Abraham T; Department of Neural and Behavioral Sciences, College of Medicine, Pennsylvania State University, Hershey, PA, USA., Shepherd TG; The Mary & John Knight Translational Ovarian Cancer Research Unit, Departments of Obstetrics & Gynecology Oncology and Anatomy & Cell Biology, Western University, London, ON, Canada., Warrick JI; Department of Pathology, College of Medicine, Pennsylvania State University, Hershey, PA, USA., Lee NY; Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA., Phaeton R; Department of Obstetrics and Gynecology, and Microbiology and Immunology, College of Medicine, Pennsylvania State University, Hershey, PA, USA., Mythreye K; Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA. mythreye@uab.edu.; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA. mythreye@uab.edu., Hempel N; Department of Pharmacology, College of Medicine, Pennsylvania State University, Hershey, PA, USA. nhempel@psu.edu.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2020 Feb; Vol. 39 (8), pp. 1619-1633. Date of Electronic Publication: 2019 Nov 13.
DOI: 10.1038/s41388-019-1097-7
Abstrakt: Tumor cells must alter their antioxidant capacity for maximal metastatic potential. Yet the antioxidant adaptations required for ovarian cancer transcoelomic metastasis, which is the passive dissemination of cells in the peritoneal cavity, remain largely unexplored. Somewhat contradicting the need for oxidant scavenging are previous observations that expression of SIRT3, a nutrient stress sensor and regulator of mitochondrial antioxidant defenses, is often suppressed in many primary tumors. We have discovered that this mitochondrial deacetylase is specifically upregulated in a context-dependent manner in cancer cells. SIRT3 activity and expression transiently increased following ovarian cancer cell detachment and in tumor cells derived from malignant ascites of high-grade serous adenocarcinoma patients. Mechanistically, SIRT3 prevents mitochondrial superoxide surges in detached cells by regulating the manganese superoxide dismutase (SOD2). This mitochondrial stress response is under dual regulation by SIRT3. SIRT3 rapidly increases SOD2 activity as an early adaptation to cellular detachment, which is followed by SIRT3-dependent increases in SOD2 mRNA during sustained anchorage-independence. In addition, SIRT3 inhibits glycolytic capacity in anchorage-independent cells thereby contributing to metabolic changes in response to detachment. While manipulation of SIRT3 expression has few deleterious effects on cancer cells in attached conditions, SIRT3 upregulation and SIRT3-mediated oxidant scavenging are required for anoikis resistance in vitro following matrix detachment, and both SIRT3 and SOD2 are necessary for colonization of the peritoneal cavity in vivo. Our results highlight the novel context-specific, pro-metastatic role of SIRT3 in ovarian cancer.
Databáze: MEDLINE
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