HNF1 beta drives glutathione (GSH) synthesis underlying intrinsic carboplatin resistance of ovarian clear cell carcinoma (OCCC)

Filipa Lopes-Coelho, Sofia Gouveia-Fernandes, Luis Pedro Goncalves, Carolina Nunes, Ines Faustino, Fernanda Silva, Ana Maria Felix de Campos Pinto, Sofia de Azeredo Gaspar Pereira, Jacinta Serpa

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Chemoresistance to platinum-based antineoplastic agents is a consistent feature among ovarian carcinomas; however, whereas high-grade serous carcinoma (OSC) acquires resistance during chemotherapy, ovarian clear cell carcinoma (OCCC) is intrinsically resistant. The main objective of this study was to explore, in vitro and in vivo, if hepatocyte nuclear factor 1 beta (HNF1 beta) and glutaminolysis contribute for the resistance of OCCC to carboplatin through the intrinsically increased GSH bioavailability. To disclose the role of HNF1 beta, experiments were also performed in an OSC cell line, which does not express HNF1 beta. Metabolic profiles, GSH quantification, HNF1 beta, and gamma-glutamylcysteine ligase catalytic subunit (GCLC) and modifier subunit (GCLM) expression, cell cycle, and death were assessed in ES2 cell line (OCCC) and OVCAR3 cell line (OSC); HNF1 beta knockdown was performed in ES2 and murine model of subcutaneous and peritoneal OCCC tumors was established to test buthionine sulphoxamine (BSO), as a sensitizer to carboplatin. Glutaminolysis is activated in ES2 and OVCAR3, though ES2 exclusively synthesizes amino acids and GSH. ES2 cells are more resistant to carboplatin than OVCAR3 and the abrogation of GSH production by BSO sensitizes ES2 to carboplatin. HNF1 beta regulates the expression of GCLC, but not GCLM, and consequently GSH production in ES2. In vivo, BSO prior to carboplatin reduces dramatically subcutaneous tumor size and GSH levels, as well as peritoneal dissemination. Our study discloses HNF1 beta as the mediator of intrinsic OCCC chemoresistance and sheds a light to re-explore a cancer adjuvant therapeutic approach using BSO to overcome the lack of efficient therapy in OCCC.
Original languageEnglish
Pages (from-to)4813-4829
Number of pages17
JournalTumor Biology
Volume37
Issue number4
DOIs
Publication statusPublished - Apr 2016

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Hepatocyte Nuclear Factor 1-beta
Carboplatin
Glutathione
Carcinoma
Ligases
Cell Line
Catalytic Domain
Neoplasms
Metabolome
Platinum
Antineoplastic Agents
Biological Availability
Cell Cycle
Cell Death

Cite this

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title = "HNF1 beta drives glutathione (GSH) synthesis underlying intrinsic carboplatin resistance of ovarian clear cell carcinoma (OCCC)",
abstract = "Chemoresistance to platinum-based antineoplastic agents is a consistent feature among ovarian carcinomas; however, whereas high-grade serous carcinoma (OSC) acquires resistance during chemotherapy, ovarian clear cell carcinoma (OCCC) is intrinsically resistant. The main objective of this study was to explore, in vitro and in vivo, if hepatocyte nuclear factor 1 beta (HNF1 beta) and glutaminolysis contribute for the resistance of OCCC to carboplatin through the intrinsically increased GSH bioavailability. To disclose the role of HNF1 beta, experiments were also performed in an OSC cell line, which does not express HNF1 beta. Metabolic profiles, GSH quantification, HNF1 beta, and gamma-glutamylcysteine ligase catalytic subunit (GCLC) and modifier subunit (GCLM) expression, cell cycle, and death were assessed in ES2 cell line (OCCC) and OVCAR3 cell line (OSC); HNF1 beta knockdown was performed in ES2 and murine model of subcutaneous and peritoneal OCCC tumors was established to test buthionine sulphoxamine (BSO), as a sensitizer to carboplatin. Glutaminolysis is activated in ES2 and OVCAR3, though ES2 exclusively synthesizes amino acids and GSH. ES2 cells are more resistant to carboplatin than OVCAR3 and the abrogation of GSH production by BSO sensitizes ES2 to carboplatin. HNF1 beta regulates the expression of GCLC, but not GCLM, and consequently GSH production in ES2. In vivo, BSO prior to carboplatin reduces dramatically subcutaneous tumor size and GSH levels, as well as peritoneal dissemination. Our study discloses HNF1 beta as the mediator of intrinsic OCCC chemoresistance and sheds a light to re-explore a cancer adjuvant therapeutic approach using BSO to overcome the lack of efficient therapy in OCCC.",
author = "Filipa Lopes-Coelho and Sofia Gouveia-Fernandes and Goncalves, {Luis Pedro} and Carolina Nunes and Ines Faustino and Fernanda Silva and Pinto, {Ana Maria Felix de Campos} and Pereira, {Sofia de Azeredo Gaspar} and Jacinta Serpa",
year = "2016",
month = "4",
doi = "10.1007/s13277-015-4290-5",
language = "English",
volume = "37",
pages = "4813--4829",
journal = "Tumor Biology",
issn = "1010-4283",
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number = "4",

}

HNF1 beta drives glutathione (GSH) synthesis underlying intrinsic carboplatin resistance of ovarian clear cell carcinoma (OCCC). / Lopes-Coelho, Filipa; Gouveia-Fernandes, Sofia; Goncalves, Luis Pedro; Nunes, Carolina; Faustino, Ines; Silva, Fernanda; Pinto, Ana Maria Felix de Campos; Pereira, Sofia de Azeredo Gaspar; Serpa, Jacinta.

In: Tumor Biology, Vol. 37, No. 4, 04.2016, p. 4813-4829.

Research output: Contribution to journalArticle

TY - JOUR

T1 - HNF1 beta drives glutathione (GSH) synthesis underlying intrinsic carboplatin resistance of ovarian clear cell carcinoma (OCCC)

AU - Lopes-Coelho, Filipa

AU - Gouveia-Fernandes, Sofia

AU - Goncalves, Luis Pedro

AU - Nunes, Carolina

AU - Faustino, Ines

AU - Silva, Fernanda

AU - Pinto, Ana Maria Felix de Campos

AU - Pereira, Sofia de Azeredo Gaspar

AU - Serpa, Jacinta

PY - 2016/4

Y1 - 2016/4

N2 - Chemoresistance to platinum-based antineoplastic agents is a consistent feature among ovarian carcinomas; however, whereas high-grade serous carcinoma (OSC) acquires resistance during chemotherapy, ovarian clear cell carcinoma (OCCC) is intrinsically resistant. The main objective of this study was to explore, in vitro and in vivo, if hepatocyte nuclear factor 1 beta (HNF1 beta) and glutaminolysis contribute for the resistance of OCCC to carboplatin through the intrinsically increased GSH bioavailability. To disclose the role of HNF1 beta, experiments were also performed in an OSC cell line, which does not express HNF1 beta. Metabolic profiles, GSH quantification, HNF1 beta, and gamma-glutamylcysteine ligase catalytic subunit (GCLC) and modifier subunit (GCLM) expression, cell cycle, and death were assessed in ES2 cell line (OCCC) and OVCAR3 cell line (OSC); HNF1 beta knockdown was performed in ES2 and murine model of subcutaneous and peritoneal OCCC tumors was established to test buthionine sulphoxamine (BSO), as a sensitizer to carboplatin. Glutaminolysis is activated in ES2 and OVCAR3, though ES2 exclusively synthesizes amino acids and GSH. ES2 cells are more resistant to carboplatin than OVCAR3 and the abrogation of GSH production by BSO sensitizes ES2 to carboplatin. HNF1 beta regulates the expression of GCLC, but not GCLM, and consequently GSH production in ES2. In vivo, BSO prior to carboplatin reduces dramatically subcutaneous tumor size and GSH levels, as well as peritoneal dissemination. Our study discloses HNF1 beta as the mediator of intrinsic OCCC chemoresistance and sheds a light to re-explore a cancer adjuvant therapeutic approach using BSO to overcome the lack of efficient therapy in OCCC.

AB - Chemoresistance to platinum-based antineoplastic agents is a consistent feature among ovarian carcinomas; however, whereas high-grade serous carcinoma (OSC) acquires resistance during chemotherapy, ovarian clear cell carcinoma (OCCC) is intrinsically resistant. The main objective of this study was to explore, in vitro and in vivo, if hepatocyte nuclear factor 1 beta (HNF1 beta) and glutaminolysis contribute for the resistance of OCCC to carboplatin through the intrinsically increased GSH bioavailability. To disclose the role of HNF1 beta, experiments were also performed in an OSC cell line, which does not express HNF1 beta. Metabolic profiles, GSH quantification, HNF1 beta, and gamma-glutamylcysteine ligase catalytic subunit (GCLC) and modifier subunit (GCLM) expression, cell cycle, and death were assessed in ES2 cell line (OCCC) and OVCAR3 cell line (OSC); HNF1 beta knockdown was performed in ES2 and murine model of subcutaneous and peritoneal OCCC tumors was established to test buthionine sulphoxamine (BSO), as a sensitizer to carboplatin. Glutaminolysis is activated in ES2 and OVCAR3, though ES2 exclusively synthesizes amino acids and GSH. ES2 cells are more resistant to carboplatin than OVCAR3 and the abrogation of GSH production by BSO sensitizes ES2 to carboplatin. HNF1 beta regulates the expression of GCLC, but not GCLM, and consequently GSH production in ES2. In vivo, BSO prior to carboplatin reduces dramatically subcutaneous tumor size and GSH levels, as well as peritoneal dissemination. Our study discloses HNF1 beta as the mediator of intrinsic OCCC chemoresistance and sheds a light to re-explore a cancer adjuvant therapeutic approach using BSO to overcome the lack of efficient therapy in OCCC.

U2 - 10.1007/s13277-015-4290-5

DO - 10.1007/s13277-015-4290-5

M3 - Article

VL - 37

SP - 4813

EP - 4829

JO - Tumor Biology

JF - Tumor Biology

SN - 1010-4283

IS - 4

ER -