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.

Polyurea Dendrimer Folate-Targeted Nanodelivery of l-Buthionine Sulfoximine as a Tool to Tackle Ovarian Cancer Chemoresistance

“…In the future, this approach may be applied to other chemoresistant cancers. Our previous studies suggested a stronger dependence of ES2 cells on GSH turnover compared with OVCAR3 cells [12,13], which was also evidenced in this study, as higher EC 50 of free l-BSO and l-BSO@PURE G4 -FA 2 were determined for ES2 compared with OVCAR3 cells. Furthermore, concerning resistance to carboplatin, we have reported that upon carboplatin exposure ES2 produce higher levels of GSH [11] together with an accelerated GSH turnover, compared with OVCAR3 [28].…”

“…Therefore, the development of strategies to overcome chemoresistance is required for a more effective treatment of ovarian cancer [8,15,32,33]. Following our insights on ovarian cancer metabolic remodeling and therapy response [11][12][13], we posited that a FA-Rα-targeted delivery of l-BSO can be a promising strategy to revoke resistance to carboplatin (Figure 6).…”

“…The platinum drugs induce cell death through two mechanisms: the establishment of adducts of DNA and proteins, and the generation of reactive oxygen species (ROS) [9,10]. We have previously found that ovarian cancer cells exhibit a great metabolic reliance on cysteine and glutathione (GSH), as these thiols were shown to protect cells under stressful conditions such as hypoxia or carboplatin exposure, hence, also accounting for chemoresistance [11][12][13]. GSH can explain this protective effect given its role as a ROS scavenger and as a pivotal drug detoxifier, allowing cells to evade cell death [14][15][16][17][18].…”

Monocytes as Endothelial Progenitor Cells (EPCs), Another Brick in the Wall to Disentangle Tumor Angiogenesis

“…Recently, in studies dedicated to cancer metabolism, our team showed that cysteine is beneficial for cells coping with ROS [67,68]. In monocytes, cysteine seemed to have the same role, by protecting cells against ROS effects.…”

Sox2 promotes expression of the ST6Gal-I glycosyltransferase in ovarian cancer cells

“…While most ovarian cancer patients respond initially to treatment, acquired resistance is common, leading to tumor recurrence [2]. Cancer stem cells (CSCs) are thought to be principal drivers of ovarian cancer progression and recurrence due to their high degree of resistance to both chemotherapy and microenvironmental stressors such as hypoxia [3,4]. Thus, extensive research is focused on the molecular mechanisms that promote a CSC phenotype.…”