Cysteine boosters the evolutionary adaptation to CoCl2 mimicked hypoxia conditions, favouring carboplatin resistance in ovarian cancer

Abstract

BackgroundOvarian cancer is the second most common gynaecologic malignancy and the most common cause of death from gynaecologic cancer, especially due to diagnosis at an advanced stage, when a cure is rare. As ovarian tumour grows, cancer cells are exposed to regions of hypoxia. Hypoxia is known to be partially responsible for tumour progression, metastasis and resistance to therapies. These suggest that hypoxia entails a selective pressure in which the adapted cells not only have a fitness increase under the selective environment, but also in non-selective adverse environments. In here, we used two different ovarian cancer cell lines – serous carcinoma (OVCAR3) and clear cell carcinoma (ES2) – in order to address the effect of cancer cells selection under normoxia and hypoxia mimicked by cobalt chloride on the evolutionary outcome of cancer cells.ResultsOur results showed that the adaptation to normoxia and CoCl2 mimicked hypoxia leads cells to display opposite strategies. Whereas cells adapted to CoCl2 mimicked hypoxia conditions tend to proliferate less but present increased survival in adverse environments, cells adapted to normoxia proliferate rapidly but at the cost of increased mortality in adverse environments. Moreover, results suggest that cysteine allows a quicker response and adaptation to hypoxic conditions that, in turn, are capable of driving chemoresistance.ConclusionsWe showed that cysteine impacts the adaptation of cancer cells to a CoCl2 mimicked hypoxic environment thus contributing for hypoxia-drived platinum-based chemotherapeutic agents’ resistance, allowing the selection of more aggressive phenotypes. These observations support a role of cysteine in cancer progression, recurrence and chemoresistance.Electronic supplementary materialThe online version of this article (10.1186/s12862-018-1214-1) contains supplementary material, which is available to authorized users.

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.…”

Cysteine Aminotransferase (CAT): A Pivotal Sponsor in Metabolic Remodeling and an Ally of 3-Mercaptopyruvate Sulfurtransferase (MST) in Cancer

“…Among different adaptive strategies adopted by chemoresistant cancer cells, chemoresistance has been associated with alterations in glutathione (GSH) and cysteine dynamics. We and others showed that, overall, cysteine flux in cancer cells and the expression and activity of enzymes involved in cysteine metabolism interfere with the response to chemotherapy by ultimately abrogating the effect of oxidative or alkylating drugs [ 3 , 4 , 5 , 6 , 7 ]. On the other hand, enzymes function is influenced by the oxidative stress.…”