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 o...

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Autores principales:	Sofia C. Nunes, Cristiano Ramos, Filipa Lopes-Coelho, Catarina O. Sequeira, Fernanda Silva, Sofia Gouveia-Fernandes, Armanda Rodrigues, António Guimarães, Margarida Silveira, Sofia Abreu, Vítor E. Santo, Catarina Brito, Ana Félix, Sofia A. Pereira, Jacinta Serpa
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f0b992f1098b47c99c388b7bc002b953
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spelling	oai:doaj.org-article:f0b992f1098b47c99c388b7bc002b9532021-12-02T15:09:08ZCysteine allows ovarian cancer cells to adapt to hypoxia and to escape from carboplatin cytotoxicity10.1038/s41598-018-27753-y2045-2322https://doaj.org/article/f0b992f1098b47c99c388b7bc002b9532018-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-27753-yhttps://doaj.org/toc/2045-2322Abstract 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.Sofia C. NunesCristiano RamosFilipa Lopes-CoelhoCatarina O. SequeiraFernanda SilvaSofia Gouveia-FernandesArmanda RodriguesAntónio GuimarãesMargarida SilveiraSofia AbreuVítor E. SantoCatarina BritoAna FélixSofia A. PereiraJacinta SerpaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-17 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sofia C. Nunes Cristiano Ramos Filipa Lopes-Coelho Catarina O. Sequeira Fernanda Silva Sofia Gouveia-Fernandes Armanda Rodrigues António Guimarães Margarida Silveira Sofia Abreu Vítor E. Santo Catarina Brito Ana Félix Sofia A. Pereira Jacinta Serpa Cysteine allows ovarian cancer cells to adapt to hypoxia and to escape from carboplatin cytotoxicity
description	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.
format	article
author	Sofia C. Nunes Cristiano Ramos Filipa Lopes-Coelho Catarina O. Sequeira Fernanda Silva Sofia Gouveia-Fernandes Armanda Rodrigues António Guimarães Margarida Silveira Sofia Abreu Vítor E. Santo Catarina Brito Ana Félix Sofia A. Pereira Jacinta Serpa
author_facet	Sofia C. Nunes Cristiano Ramos Filipa Lopes-Coelho Catarina O. Sequeira Fernanda Silva Sofia Gouveia-Fernandes Armanda Rodrigues António Guimarães Margarida Silveira Sofia Abreu Vítor E. Santo Catarina Brito Ana Félix Sofia A. Pereira Jacinta Serpa
author_sort	Sofia C. Nunes
title	Cysteine allows ovarian cancer cells to adapt to hypoxia and to escape from carboplatin cytotoxicity
title_short	Cysteine allows ovarian cancer cells to adapt to hypoxia and to escape from carboplatin cytotoxicity
title_full	Cysteine allows ovarian cancer cells to adapt to hypoxia and to escape from carboplatin cytotoxicity
title_fullStr	Cysteine allows ovarian cancer cells to adapt to hypoxia and to escape from carboplatin cytotoxicity
title_full_unstemmed	Cysteine allows ovarian cancer cells to adapt to hypoxia and to escape from carboplatin cytotoxicity
title_sort	cysteine allows ovarian cancer cells to adapt to hypoxia and to escape from carboplatin cytotoxicity
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/f0b992f1098b47c99c388b7bc002b953
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Cysteine allows ovarian cancer cells to adapt to hypoxia and to escape from carboplatin cytotoxicity

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