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Cysteine degradation as a sulfur to sustain oxidative phosphorylation OXPHOS in hypoxic cancer cells - new therapeutic targets.
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Cysteine, a facilitator of hypoxia adaptation and a promoter of drug-resistance : a new route to better diagnose and treat ovarian cancer patients
Publication . Nunes, Ana Sofia de Almeida da Costa; Serpa, Jacinta; Félix, Ana; Pereira, Sofia Azeredo
Ovarian cancer is the third most common gynaecologic malignancy and the main cause of death from gynaecologic cancer. Despite in the last 30 years an improvement of the overall survival of ovarian cancer patients has been observed, an increased cure rate was not registered. The high mortality associated with ovarian cancer is mainly due to a late diagnosis and resistance to treatment, barring ovarian cancer cure. Given the lack of a specific therapy against ovarian cancer, the treatment depends essentially on the use of generalised and comprehensive cytotoxic drugs, most of them belonging to the group of alkylating/oxidative agents, as platinum salts. Chemotherapy imposes high selection pressures in cancer cells, which may affect their evolutionary trajectories, selecting the chemoresistant ones, which will continue the progression and relapse of the disease, contributing to morbidity and mortality. In recent years, cancer metabolism has acquired a central position in oncobiology, being the metabolic remodelling a requirement for tumour progression, allowing cancer cells to respond to the selective Pressures of the microenvironment, such as hypoxia and cytotoxic drugs. These selective pressures promote cell death in non-adapted cells and positively select cells that exhibit growth advantage that will further sustain cancer progression and metastasis. Endogenous metabolism also limits drugs response. A role of cysteine in cancer by contributing for H2S generation and as a precursor of the antioxidant glutathione (GSH), were already reported. GSH has a crucial role as an antioxidant and also as a detoxifying system allowing the physiological maintenance of metabolic pathways, being intimately associated with chemoresistance. H2S is involved in several biological processes, acting also as an antioxidant and being associated with cancer progression and chemoresistance. As a solid tumour grows, such as an ovarian tumour, due to inefficient vascularisation, cancer cells are exposed to regions of hypoxia, known as a boost factor for tumour progression, metastasis and resistance to therapy.
The present thesis aimed to clarify the relevance of cysteine metabolism in ovarian cancer cells adaptability to both hypoxia and platinum salts (carboplatin). These stressful conditions impose strong evolutionary selection pressure on cancer cells. Our results have provided evidence that cysteine metabolism has a role in ovarian cancer cells fast response and adaptation to hypoxic conditions that, in turn, are capable of driving chemoresistance. Moreover, cysteine showed to present a widespread protective effect against both hypoxia and carboplatininduced death among ovarian cancer cell lines. Importantly, our findings were also supported in a clinical context, as an overall increase of thiols concentration was found in serum from patients with ovarian neoplasms, regardless malignancy. Strikingly, the free levels of cysteine together with protein-Scysteinylation levels were able to distinguish patients with malignant tumours from patients with benign tumours and also from healthy individuals, supporting that the levels of cysteine and protein-S-cysteinylation can be putative biomarkers for ovarian cancer early diagnosis. Cysteine was also the prevalent thiol and Scysteinylation was the most abundant form of S-thiolated proteins in the ascitic fluid from patients with advanced disease. The ascitic fluid is an important compartment of the ovarian cancer cells microenvironment, supporting a clinical relevance of cysteine also in the progression of the disease. Given the protective effect of cysteine in hypoxic ovarian cancer cells, we also aimed to address the possible mechanisms by which cysteine would be beneficial under hypoxia. Our results have supported a role of a higher thiols turnover in the adaptation to this environment, especially in ES2 cells. Moreover, results have also supported a role of cysteine in energy production mediated by the xc- system, that requires cysteine metabolism instead of H2S per se. However, the direct role of cysteine in ATP production is still uncertain as this amino acid can have an indirect contribution to ATP synthesis driven by an increased GSH content, allowing the redox equilibrium crucial for the overall cellular metabolism. Strikingly, 1H-NMR results have suggested that cysteine impacted profoundly ES2 cells metabolism under hypoxia, allowing a metabolic reprogramming, that probably underlies ES2 cells adaptation to hypoxia. Taken together, this thesis has shed light on new paths for ovarian cancer screening, diagnosis, prognosis and therapy, where cysteine metabolic profile might allow the design of new and useful approaches to fight this disease, thus overcoming its poor prognosis.
Cysteine boosters the evolutionary adaptation to CoCl2 mimicked hypoxia conditions, favouring carboplatin resistance in ovarian cancer
Publication . Nunes, Sofia C.; Lopes-Coelho, Filipa; Gouveia-Fernandes, Sofia; Ramos, Cristiano; Pereira, Sofia A.; SA, Pereira; Serpa, Jacinta; Serpa, Jacinta; NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM); Centro de Estudos de Doenças Crónicas (CEDOC); Springer Verlag
Background: Ovarian 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. Results: Our 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. Conclusions: We 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.
Glutathione in Ovarian Cancer
Publication . Nunes, Sofia C.; Serpa, Jacinta; Serpa, Jacinta; Centro de Estudos de Doenças Crónicas (CEDOC); MDPI - Multidisciplinary Digital Publishing Institute
Glutathione (GSH) has several roles in a cell, such as a reactive oxygen species (ROS) scavenger, an intervenient in xenobiotics metabolism and a reservoir of cysteine. All of these activities are important in the maintenance of normal cells homeostasis but can also constitute an advantage for cancer cells, allowing disease progression and resistance to therapy. Ovarian cancer is the major cause of death from gynaecologic disease and the second most common gynaecologic malignancy worldwide. In over 50 years, the overall survival of patients diagnosed with epithelial ovarian cancer has not changed, regardless of the efforts concerning early detection, radical surgery and new therapeutic approaches. Late diagnosis and resistance to therapy are the main causes of this outcome, and GSH is profoundly associated with chemoresistance to platinum salts, which, together with taxane-based chemotherapy and surgery, are the main therapy strategies in ovarian cancer treatment. Herein, we present some insights into the role of GSH in the poor prognosis of ovarian cancer, and also point out how some strategies underlying the dependence of ovarian cancer cells on GSH can be further used to improve the effectiveness of therapy.
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Fundação para a Ciência e a Tecnologia
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PD/BD/105893/2014