Abstract

Ovarian cancer remains the most lethal gynecologic malignancy, and is primarily diagnosed at late stage when considerable metastasis has occurred in the peritoneal cavity. At late stage abdominal cavity ascites accumulation provides a tumor-supporting medium in which cancer cells gain access to growth factors and cytokines that promote survival and metastasis. However, little is known about the redox status of ascites, or whether antioxidant enzymes are required to support ovarian cancer survival during transcoelomic metastasis in this medium. Gene expression cluster analysis of antioxidant enzymes identified two distinct populations of high-grade serous adenocarcinomas (HGSA), the most common ovarian cancer subtype, which specifically separated into clusters based on glutathione peroxidase 3 (GPx3) expression. High GPx3 expression was associated with poorer overall patient survival and increased tumor stage. GPx3 is an extracellular glutathione peroxidase with reported dichotomous roles in cancer. To further examine a potential pro-tumorigenic role of GPx3 in HGSA, stable OVCAR3 GPx3 knock-down cell lines were generated using lentiviral shRNA constructs. Decreased GPx3 expression inhibited clonogenicity and anchorage-independent cell survival. Moreover, GPx3 was necessary for protecting cells from exogenous oxidant insult, as demonstrated by treatment with high dose ascorbate. This cytoprotective effect was shown to be due to GPx3-dependent removal of extracellular H2O2. Importantly, GPx3 was necessary for clonogenic survival when cells were cultured in patient-derived ascites fluid. While oxidation reduction potential (ORP) of malignant ascites was heterogeneous in our patient cohort, and correlated positively with ascites iron content, GPx3 was required for optimal survival regardless of ORP or iron content. Collectively, our data suggest that HGSA ovarian cancers cluster into distinct groups of high and low GPx3 expression. GPx3 is necessary for HGSA ovarian cancer cellular survival in the ascites tumor environment and protects against extracellular sources of oxidative stress, implicating GPx3 as an important adaptation for transcoelomic metastasis.

Original languageEnglish (US)
Article number101051
JournalRedox Biology
Volume25
DOIs
StatePublished - Jul 2019

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Glutathione Peroxidase
Ovarian Neoplasms
Oxidation-Reduction
Ascites
Adenocarcinoma
Survival
Neoplasm Metastasis
Tumors
Neoplasms
Cells
Cell Survival
Iron
Antioxidants
Oxidative stress
Abdominal Cavity
Peritoneal Cavity
Cluster analysis
Enzymes
Multigene Family
Oxidants

All Science Journal Classification (ASJC) codes

  • Organic Chemistry
  • Clinical Biochemistry

Cite this

Worley, Beth L. ; Kim, Yeon Soo ; Mardini, Jennifer ; Zaman, Rameez ; Leon, Kelly E. ; Vallur, Piyushi Gupta ; Nduwumwami, Asvelt ; Warrick, Joshua I. ; Timmins, Patrick F. ; Kesterson, Joshua P. ; Phaëton, Rébécca ; Lee, Nam Y. ; Walter, Vonn ; Endres, Lauren ; Mythreye, Karthikeyan ; Aird, Katherine M. ; Hempel, Nadine. / GPx3 supports ovarian cancer progression by manipulating the extracellular redox environment. In: Redox Biology. 2019 ; Vol. 25.
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title = "GPx3 supports ovarian cancer progression by manipulating the extracellular redox environment",
abstract = "Ovarian cancer remains the most lethal gynecologic malignancy, and is primarily diagnosed at late stage when considerable metastasis has occurred in the peritoneal cavity. At late stage abdominal cavity ascites accumulation provides a tumor-supporting medium in which cancer cells gain access to growth factors and cytokines that promote survival and metastasis. However, little is known about the redox status of ascites, or whether antioxidant enzymes are required to support ovarian cancer survival during transcoelomic metastasis in this medium. Gene expression cluster analysis of antioxidant enzymes identified two distinct populations of high-grade serous adenocarcinomas (HGSA), the most common ovarian cancer subtype, which specifically separated into clusters based on glutathione peroxidase 3 (GPx3) expression. High GPx3 expression was associated with poorer overall patient survival and increased tumor stage. GPx3 is an extracellular glutathione peroxidase with reported dichotomous roles in cancer. To further examine a potential pro-tumorigenic role of GPx3 in HGSA, stable OVCAR3 GPx3 knock-down cell lines were generated using lentiviral shRNA constructs. Decreased GPx3 expression inhibited clonogenicity and anchorage-independent cell survival. Moreover, GPx3 was necessary for protecting cells from exogenous oxidant insult, as demonstrated by treatment with high dose ascorbate. This cytoprotective effect was shown to be due to GPx3-dependent removal of extracellular H2O2. Importantly, GPx3 was necessary for clonogenic survival when cells were cultured in patient-derived ascites fluid. While oxidation reduction potential (ORP) of malignant ascites was heterogeneous in our patient cohort, and correlated positively with ascites iron content, GPx3 was required for optimal survival regardless of ORP or iron content. Collectively, our data suggest that HGSA ovarian cancers cluster into distinct groups of high and low GPx3 expression. GPx3 is necessary for HGSA ovarian cancer cellular survival in the ascites tumor environment and protects against extracellular sources of oxidative stress, implicating GPx3 as an important adaptation for transcoelomic metastasis.",
author = "Worley, {Beth L.} and Kim, {Yeon Soo} and Jennifer Mardini and Rameez Zaman and Leon, {Kelly E.} and Vallur, {Piyushi Gupta} and Asvelt Nduwumwami and Warrick, {Joshua I.} and Timmins, {Patrick F.} and Kesterson, {Joshua P.} and R{\'e}b{\'e}cca Pha{\"e}ton and Lee, {Nam Y.} and Vonn Walter and Lauren Endres and Karthikeyan Mythreye and Aird, {Katherine M.} and Nadine Hempel",
year = "2019",
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doi = "10.1016/j.redox.2018.11.009",
language = "English (US)",
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journal = "Redox Biology",
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Worley, BL, Kim, YS, Mardini, J, Zaman, R, Leon, KE, Vallur, PG, Nduwumwami, A, Warrick, JI, Timmins, PF, Kesterson, JP, Phaëton, R, Lee, NY, Walter, V, Endres, L, Mythreye, K, Aird, KM & Hempel, N 2019, 'GPx3 supports ovarian cancer progression by manipulating the extracellular redox environment', Redox Biology, vol. 25, 101051. https://doi.org/10.1016/j.redox.2018.11.009

GPx3 supports ovarian cancer progression by manipulating the extracellular redox environment. / Worley, Beth L.; Kim, Yeon Soo; Mardini, Jennifer; Zaman, Rameez; Leon, Kelly E.; Vallur, Piyushi Gupta; Nduwumwami, Asvelt; Warrick, Joshua I.; Timmins, Patrick F.; Kesterson, Joshua P.; Phaëton, Rébécca; Lee, Nam Y.; Walter, Vonn; Endres, Lauren; Mythreye, Karthikeyan; Aird, Katherine M.; Hempel, Nadine.

In: Redox Biology, Vol. 25, 101051, 07.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - GPx3 supports ovarian cancer progression by manipulating the extracellular redox environment

AU - Worley, Beth L.

AU - Kim, Yeon Soo

AU - Mardini, Jennifer

AU - Zaman, Rameez

AU - Leon, Kelly E.

AU - Vallur, Piyushi Gupta

AU - Nduwumwami, Asvelt

AU - Warrick, Joshua I.

AU - Timmins, Patrick F.

AU - Kesterson, Joshua P.

AU - Phaëton, Rébécca

AU - Lee, Nam Y.

AU - Walter, Vonn

AU - Endres, Lauren

AU - Mythreye, Karthikeyan

AU - Aird, Katherine M.

AU - Hempel, Nadine

PY - 2019/7

Y1 - 2019/7

N2 - Ovarian cancer remains the most lethal gynecologic malignancy, and is primarily diagnosed at late stage when considerable metastasis has occurred in the peritoneal cavity. At late stage abdominal cavity ascites accumulation provides a tumor-supporting medium in which cancer cells gain access to growth factors and cytokines that promote survival and metastasis. However, little is known about the redox status of ascites, or whether antioxidant enzymes are required to support ovarian cancer survival during transcoelomic metastasis in this medium. Gene expression cluster analysis of antioxidant enzymes identified two distinct populations of high-grade serous adenocarcinomas (HGSA), the most common ovarian cancer subtype, which specifically separated into clusters based on glutathione peroxidase 3 (GPx3) expression. High GPx3 expression was associated with poorer overall patient survival and increased tumor stage. GPx3 is an extracellular glutathione peroxidase with reported dichotomous roles in cancer. To further examine a potential pro-tumorigenic role of GPx3 in HGSA, stable OVCAR3 GPx3 knock-down cell lines were generated using lentiviral shRNA constructs. Decreased GPx3 expression inhibited clonogenicity and anchorage-independent cell survival. Moreover, GPx3 was necessary for protecting cells from exogenous oxidant insult, as demonstrated by treatment with high dose ascorbate. This cytoprotective effect was shown to be due to GPx3-dependent removal of extracellular H2O2. Importantly, GPx3 was necessary for clonogenic survival when cells were cultured in patient-derived ascites fluid. While oxidation reduction potential (ORP) of malignant ascites was heterogeneous in our patient cohort, and correlated positively with ascites iron content, GPx3 was required for optimal survival regardless of ORP or iron content. Collectively, our data suggest that HGSA ovarian cancers cluster into distinct groups of high and low GPx3 expression. GPx3 is necessary for HGSA ovarian cancer cellular survival in the ascites tumor environment and protects against extracellular sources of oxidative stress, implicating GPx3 as an important adaptation for transcoelomic metastasis.

AB - Ovarian cancer remains the most lethal gynecologic malignancy, and is primarily diagnosed at late stage when considerable metastasis has occurred in the peritoneal cavity. At late stage abdominal cavity ascites accumulation provides a tumor-supporting medium in which cancer cells gain access to growth factors and cytokines that promote survival and metastasis. However, little is known about the redox status of ascites, or whether antioxidant enzymes are required to support ovarian cancer survival during transcoelomic metastasis in this medium. Gene expression cluster analysis of antioxidant enzymes identified two distinct populations of high-grade serous adenocarcinomas (HGSA), the most common ovarian cancer subtype, which specifically separated into clusters based on glutathione peroxidase 3 (GPx3) expression. High GPx3 expression was associated with poorer overall patient survival and increased tumor stage. GPx3 is an extracellular glutathione peroxidase with reported dichotomous roles in cancer. To further examine a potential pro-tumorigenic role of GPx3 in HGSA, stable OVCAR3 GPx3 knock-down cell lines were generated using lentiviral shRNA constructs. Decreased GPx3 expression inhibited clonogenicity and anchorage-independent cell survival. Moreover, GPx3 was necessary for protecting cells from exogenous oxidant insult, as demonstrated by treatment with high dose ascorbate. This cytoprotective effect was shown to be due to GPx3-dependent removal of extracellular H2O2. Importantly, GPx3 was necessary for clonogenic survival when cells were cultured in patient-derived ascites fluid. While oxidation reduction potential (ORP) of malignant ascites was heterogeneous in our patient cohort, and correlated positively with ascites iron content, GPx3 was required for optimal survival regardless of ORP or iron content. Collectively, our data suggest that HGSA ovarian cancers cluster into distinct groups of high and low GPx3 expression. GPx3 is necessary for HGSA ovarian cancer cellular survival in the ascites tumor environment and protects against extracellular sources of oxidative stress, implicating GPx3 as an important adaptation for transcoelomic metastasis.

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