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.
Highlights
Ovarian cancer is a group of distinct diseases that have a common anatomical location[1] and it is the major cause of death from gynaecologic cancer and the second most common gynaecologic malignancy worldwide[2,3]
The outcome prognosis of different histological types of ovarian cancer had been a matter of debate, it was shown that patients with OCCC had a significantly worse prognosis than patients with OSC when matched for age, stage, and level of primary cytoreduction[31]
Several ovarian cancer cell lines were used and major differences were found on cysteine dependence on copping with hypoxia and carboplatin
Summary
Ovarian cancer is a group of distinct diseases that have a common anatomical location[1] and it is the major cause of death from gynaecologic cancer and the second most common gynaecologic malignancy worldwide[2,3]. The inhibition of GSH synthesis by buthionine sulphoximine (BSO) sensitized OCCC cells to carboplatin[23] Chemoresistance in those cells might be associated with thiols dynamics. As hypoxia can be a mean of selecting more aggressive resistant cancer cells, we hypothesised that cysteine favours the adaptation to hypoxic conditions and chemotherapeutic agents, having a pivotal role in tumour progression, recurrence and chemoresistance. To test this hypothesis, we used several ovarian cancer cell lines, including serous carcinoma (OSC - OVCAR3 and OVCAR8), sensitive and resistant to Cisplatin A2780 (A2780 parental and A2780 cisR) unspecified histotype ovarian carcinoma cells and clear cell carcinoma (OCCC-ES2) cells. To better clarify the relevance of cysteine and other thiols in ovarian cancer, we analysed their levels in peripheral blood serum from patients with benign and malignant tumours, from healthy individuals and in ascitic fluid from ovarian cancer patients
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