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

Yeon Soo Kim, Piyushi Gupta Vallur, Victoria M. Jones, Beth L. Worley, Sara Shimko, Dong Hui Shin, La Taijah C. Crawford, Chi Wei Chen, Katherine M. Aird, Thomas Abraham, Trevor G. Shepherd, Joshua I. Warrick, Nam Y. Lee, Rebecca Phaeton, Karthikeyan Mythreye, Nadine Hempel

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalOncogene
DOIs
StateAccepted/In press - Jan 1 2019

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Ovarian Neoplasms
Neoplasm Metastasis
Survival
Antioxidants
Peritoneal Cavity
Neoplasms
Oxidants
Anoikis
Ascites
Superoxides
Superoxide Dismutase
Adenocarcinoma
Up-Regulation
Food
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Kim, Yeon Soo ; Gupta Vallur, Piyushi ; Jones, Victoria M. ; Worley, Beth L. ; Shimko, Sara ; Shin, Dong Hui ; Crawford, La Taijah C. ; Chen, Chi Wei ; Aird, Katherine M. ; Abraham, Thomas ; Shepherd, Trevor G. ; Warrick, Joshua I. ; Lee, Nam Y. ; Phaeton, Rebecca ; Mythreye, Karthikeyan ; Hempel, Nadine. / Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells. In: Oncogene. 2019.
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abstract = "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.",
author = "Kim, {Yeon Soo} and {Gupta Vallur}, Piyushi and Jones, {Victoria M.} and Worley, {Beth L.} and Sara Shimko and Shin, {Dong Hui} and Crawford, {La Taijah C.} and Chen, {Chi Wei} and Aird, {Katherine M.} and Thomas Abraham and Shepherd, {Trevor G.} and Warrick, {Joshua I.} and Lee, {Nam Y.} and Rebecca Phaeton and Karthikeyan Mythreye and Nadine Hempel",
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Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells. / Kim, Yeon Soo; Gupta Vallur, Piyushi; Jones, Victoria M.; Worley, Beth L.; Shimko, Sara; Shin, Dong Hui; Crawford, La Taijah C.; Chen, Chi Wei; Aird, Katherine M.; Abraham, Thomas; Shepherd, Trevor G.; Warrick, Joshua I.; Lee, Nam Y.; Phaeton, Rebecca; Mythreye, Karthikeyan; Hempel, Nadine.

In: Oncogene, 01.01.2019.

Research output: Contribution to journalArticle

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T1 - Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells

AU - Kim, Yeon Soo

AU - Gupta Vallur, Piyushi

AU - Jones, Victoria M.

AU - Worley, Beth L.

AU - Shimko, Sara

AU - Shin, Dong Hui

AU - Crawford, La Taijah C.

AU - Chen, Chi Wei

AU - Aird, Katherine M.

AU - Abraham, Thomas

AU - Shepherd, Trevor G.

AU - Warrick, Joshua I.

AU - Lee, Nam Y.

AU - Phaeton, Rebecca

AU - Mythreye, Karthikeyan

AU - Hempel, Nadine

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