Cysteine allows ovarian cancer cells to adapt to hypoxia and to escape from carboplatin cytotoxicity

Sofia C. Nunes, Cristiano Ramos, Filipa Lopes-Coelho, Catarina O Sequeira, Fernanda Silva, Sofia Gouveia-Fernandes, Armanda Rodrigues, António Guimarães, Margarida Silveira, Vítor E Santo, Sofia Abreu, Catarina Brito, Ana Félix, Sofia A Pereira, Jacinta Serpa

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Abstract

Ovarian cancer is the second most common gynaecologic malignancy and the main cause of death from gynaecologic cancer, due to late diagnosis and chemoresistance. Studies have reported the role of cysteine in cancer, by contributing for hydrogen sulphide (H2S) generation and as a precursor of glutathione (GSH). However, the role of cysteine in the adaptation to hypoxia and therapy response remains unclear. We used several ovarian cancer cell lines, ES2, OVCAR3, OVCAR8, A2780 and A2780cisR, to clarify cysteine relevance in ovarian cancer cells survival upon hypoxia and carboplatin. Results show that ES2 and OVCAR8 cells presented a stronger dependence on cysteine availability upon hypoxia and carboplatin exposure than OVCAR3 cells. Interestingly, the A2780 cisR, but not A2780 parental cells, benefits from cysteine upon carboplatin exposure, showing that cysteine is crucial for chemoresistance. Moreover, GSH degradation and subsequent cysteine recycling pathway is associated with ovarian cancer as seen in peripheral blood serum from patients. Higher levels of total free cysteine (Cys) and homocysteine (HCys) were found in ovarian cancer patients in comparison with benign tumours and lower levels of GSH were found in ovarian neoplasms patients in comparison with healthy individuals. Importantly, the total and S-Homocysteinylated levels distinguished blood donors from patients with neoplasms as well as patients with benign from patients with malignant tumours. The levels of S-cysteinylated proteins distinguish blood donors from patients with neoplasms and the free levels of Cys in serum distinguish blood from patients with benign tumours from patients with malignant tumours. Herein we disclosed that cysteine contributes for a worse disease prognosis, allowing faster adaptation to hypoxia and protecting cells from carboplatin. The measurement of serum cysteine levels can be an effective tool for early diagnosis, for outcome prediction and follow up of disease progression.

Original languageEnglish
Article number9513
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - 22 Jun 2018

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Carboplatin
Ovarian Neoplasms
Cysteine
Neoplasms
Blood Donors
Hypoxia
Serum
Cell Hypoxia
Hydrogen Sulfide
Delayed Diagnosis
Protein S
Homocysteine
Glutathione
Disease Progression
Early Diagnosis
Cause of Death
Cell Survival
Cell Line

Cite this

@article{987a3c47d40d4cb4b1c412eb63d0031c,
title = "Cysteine allows ovarian cancer cells to adapt to hypoxia and to escape from carboplatin cytotoxicity",
abstract = "Ovarian cancer is the second most common gynaecologic malignancy and the main cause of death from gynaecologic cancer, due to late diagnosis and chemoresistance. Studies have reported the role of cysteine in cancer, by contributing for hydrogen sulphide (H2S) generation and as a precursor of glutathione (GSH). However, the role of cysteine in the adaptation to hypoxia and therapy response remains unclear. We used several ovarian cancer cell lines, ES2, OVCAR3, OVCAR8, A2780 and A2780cisR, to clarify cysteine relevance in ovarian cancer cells survival upon hypoxia and carboplatin. Results show that ES2 and OVCAR8 cells presented a stronger dependence on cysteine availability upon hypoxia and carboplatin exposure than OVCAR3 cells. Interestingly, the A2780 cisR, but not A2780 parental cells, benefits from cysteine upon carboplatin exposure, showing that cysteine is crucial for chemoresistance. Moreover, GSH degradation and subsequent cysteine recycling pathway is associated with ovarian cancer as seen in peripheral blood serum from patients. Higher levels of total free cysteine (Cys) and homocysteine (HCys) were found in ovarian cancer patients in comparison with benign tumours and lower levels of GSH were found in ovarian neoplasms patients in comparison with healthy individuals. Importantly, the total and S-Homocysteinylated levels distinguished blood donors from patients with neoplasms as well as patients with benign from patients with malignant tumours. The levels of S-cysteinylated proteins distinguish blood donors from patients with neoplasms and the free levels of Cys in serum distinguish blood from patients with benign tumours from patients with malignant tumours. Herein we disclosed that cysteine contributes for a worse disease prognosis, allowing faster adaptation to hypoxia and protecting cells from carboplatin. The measurement of serum cysteine levels can be an effective tool for early diagnosis, for outcome prediction and follow up of disease progression.",
author = "Nunes, {Sofia C.} and Cristiano Ramos and Filipa Lopes-Coelho and Sequeira, {Catarina O} and Fernanda Silva and Sofia Gouveia-Fernandes and Armanda Rodrigues and Ant{\'o}nio Guimar{\~a}es and Margarida Silveira and Santo, {V{\'i}tor E} and Sofia Abreu and Catarina Brito and Ana F{\'e}lix and Pereira, {Sofia A} and Jacinta Serpa",
note = "info:eu-repo/grantAgreement/FCT/5876/147260/PT# The authors would like to acknowledge the Instituto Portugues de Oncologia de Lisboa Francisco Gentil (IPOLFG) for partially funding the project. We would also like to acknowledge Dr Dialina Brilhante and Dr. Teresa Guerreiro (Servico de Imuno-hemoterapia, IPOLFG) for providing blood donors samples; to Dr Humberto Goncalves (Pharmacy, IPOLFG) for paclitaxel and carboplatin preparation, and Marta Teixeira (IBET) for the technical support in 3D models. The study was also funded by Projecto TVI. This research was supported by Fundacao para a Ciencia e Tecnologia (FCT) (PhD ProRegeM program, PD/BD/105893/2014, FCT fellowship, PD/BD/105768/2014). iNOVA4Health - UID/Multi/04462/2013, a program financially supported by Fundacao para a Ciencia e Tecnologia/Ministerio da Educacao e Ciencia, through national funds and co-funded by FEDER under the PT2020 Partnership Agreement is acknowledged.",
year = "2018",
month = "6",
day = "22",
doi = "10.1038/s41598-018-27753-y",
language = "English",
volume = "8",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Cysteine allows ovarian cancer cells to adapt to hypoxia and to escape from carboplatin cytotoxicity

AU - Nunes, Sofia C.

AU - Ramos, Cristiano

AU - Lopes-Coelho, Filipa

AU - Sequeira, Catarina O

AU - Silva, Fernanda

AU - Gouveia-Fernandes, Sofia

AU - Rodrigues, Armanda

AU - Guimarães, António

AU - Silveira, Margarida

AU - Santo, Vítor E

AU - Abreu, Sofia

AU - Brito, Catarina

AU - Félix, Ana

AU - Pereira, Sofia A

AU - Serpa, Jacinta

N1 - info:eu-repo/grantAgreement/FCT/5876/147260/PT# The authors would like to acknowledge the Instituto Portugues de Oncologia de Lisboa Francisco Gentil (IPOLFG) for partially funding the project. We would also like to acknowledge Dr Dialina Brilhante and Dr. Teresa Guerreiro (Servico de Imuno-hemoterapia, IPOLFG) for providing blood donors samples; to Dr Humberto Goncalves (Pharmacy, IPOLFG) for paclitaxel and carboplatin preparation, and Marta Teixeira (IBET) for the technical support in 3D models. The study was also funded by Projecto TVI. This research was supported by Fundacao para a Ciencia e Tecnologia (FCT) (PhD ProRegeM program, PD/BD/105893/2014, FCT fellowship, PD/BD/105768/2014). iNOVA4Health - UID/Multi/04462/2013, a program financially supported by Fundacao para a Ciencia e Tecnologia/Ministerio da Educacao e Ciencia, through national funds and co-funded by FEDER under the PT2020 Partnership Agreement is acknowledged.

PY - 2018/6/22

Y1 - 2018/6/22

N2 - Ovarian cancer is the second most common gynaecologic malignancy and the main cause of death from gynaecologic cancer, due to late diagnosis and chemoresistance. Studies have reported the role of cysteine in cancer, by contributing for hydrogen sulphide (H2S) generation and as a precursor of glutathione (GSH). However, the role of cysteine in the adaptation to hypoxia and therapy response remains unclear. We used several ovarian cancer cell lines, ES2, OVCAR3, OVCAR8, A2780 and A2780cisR, to clarify cysteine relevance in ovarian cancer cells survival upon hypoxia and carboplatin. Results show that ES2 and OVCAR8 cells presented a stronger dependence on cysteine availability upon hypoxia and carboplatin exposure than OVCAR3 cells. Interestingly, the A2780 cisR, but not A2780 parental cells, benefits from cysteine upon carboplatin exposure, showing that cysteine is crucial for chemoresistance. Moreover, GSH degradation and subsequent cysteine recycling pathway is associated with ovarian cancer as seen in peripheral blood serum from patients. Higher levels of total free cysteine (Cys) and homocysteine (HCys) were found in ovarian cancer patients in comparison with benign tumours and lower levels of GSH were found in ovarian neoplasms patients in comparison with healthy individuals. Importantly, the total and S-Homocysteinylated levels distinguished blood donors from patients with neoplasms as well as patients with benign from patients with malignant tumours. The levels of S-cysteinylated proteins distinguish blood donors from patients with neoplasms and the free levels of Cys in serum distinguish blood from patients with benign tumours from patients with malignant tumours. Herein we disclosed that cysteine contributes for a worse disease prognosis, allowing faster adaptation to hypoxia and protecting cells from carboplatin. The measurement of serum cysteine levels can be an effective tool for early diagnosis, for outcome prediction and follow up of disease progression.

AB - Ovarian cancer is the second most common gynaecologic malignancy and the main cause of death from gynaecologic cancer, due to late diagnosis and chemoresistance. Studies have reported the role of cysteine in cancer, by contributing for hydrogen sulphide (H2S) generation and as a precursor of glutathione (GSH). However, the role of cysteine in the adaptation to hypoxia and therapy response remains unclear. We used several ovarian cancer cell lines, ES2, OVCAR3, OVCAR8, A2780 and A2780cisR, to clarify cysteine relevance in ovarian cancer cells survival upon hypoxia and carboplatin. Results show that ES2 and OVCAR8 cells presented a stronger dependence on cysteine availability upon hypoxia and carboplatin exposure than OVCAR3 cells. Interestingly, the A2780 cisR, but not A2780 parental cells, benefits from cysteine upon carboplatin exposure, showing that cysteine is crucial for chemoresistance. Moreover, GSH degradation and subsequent cysteine recycling pathway is associated with ovarian cancer as seen in peripheral blood serum from patients. Higher levels of total free cysteine (Cys) and homocysteine (HCys) were found in ovarian cancer patients in comparison with benign tumours and lower levels of GSH were found in ovarian neoplasms patients in comparison with healthy individuals. Importantly, the total and S-Homocysteinylated levels distinguished blood donors from patients with neoplasms as well as patients with benign from patients with malignant tumours. The levels of S-cysteinylated proteins distinguish blood donors from patients with neoplasms and the free levels of Cys in serum distinguish blood from patients with benign tumours from patients with malignant tumours. Herein we disclosed that cysteine contributes for a worse disease prognosis, allowing faster adaptation to hypoxia and protecting cells from carboplatin. The measurement of serum cysteine levels can be an effective tool for early diagnosis, for outcome prediction and follow up of disease progression.

U2 - 10.1038/s41598-018-27753-y

DO - 10.1038/s41598-018-27753-y

M3 - Article

VL - 8

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 9513

ER -