Abstract
Among gynecologic malignancies, ovarian cancer is the third most prevalent and the most common cause of death, especially due to diagnosis at an advanced stage together with resistance to therapy. As a solid tumor grows, cancer cells in the microenvironment are exposed to regions of hypoxia, a selective pressure prompting tumor progression and chemoresistance. We have previously shown that cysteine contributes to the adaptation to this hypoxic microenvironment, but the mechanisms by which cysteine protects ovarian cancer cells from hypoxia-induced death are still to be unveiled. Herein, we hypothesized that cysteine contribution relies on cellular metabolism reprogramming and energy production, being cysteine itself a metabolic source. Our results strongly supported a role of xCT symporter in energy production that requires cysteine metabolism instead of hydrogen sulfide (H2S) per se. Cysteine degradation depends on the action of the H2S-synthesizing enzymes cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and/or 3-mercaptopyruvate sulfurtransferase (MpST; together with cysteine aminotransferase, CAT). In normoxia, CBS and CSE inhibition had a mild impact on cysteine-sustained ATP production, pointing out the relevance of CAT + MpST pathway. However, in hypoxia, the concomitant inhibition of CBS and CSE had a stronger impact on ATP synthesis, thus also supporting a role of their hydrogen sulfide and/or cysteine persulfide-synthesizing activity in this stressful condition. However, the relative contributions of each of these enzymes (CBS/CSE/MpST) on cysteine-derived ATP synthesis under hypoxia remains unclear, due to the lack of specific inhibitors. Strikingly, NMR analysis strongly supported a role of cysteine in the whole cellular metabolism rewiring under hypoxia. Additionally, the use of cysteine to supply biosynthesis and bioenergetics was reinforced, bringing cysteine to the plateau of a main carbon sources in cancer. Collectively, this work supports that sulfur and carbon metabolism reprogramming underlies the adaptation to hypoxic microenvironment promoted by cysteine in ovarian cancer.
Highlights
Despite all the progresses developed in prevention and new treatment approaches, cancer corresponds to the second leading cause of death worldwide (Fitzmaurice et al, 2015)
We have previously reported that cysteine supplementation was able to protect ovarian cancer cells from hypoxia-induced death (Nunes et al, 2018a,b)
Since results have suggested that cysteine has a role in ATP production under hypoxia-mimicked conditions that can be in part related to H2S synthesis, we investigated if the impact of cysteine on ATP production rely on CBS/cystathionine γ-lyase (CSE)-catalyzed H2S production
Summary
Despite all the progresses developed in prevention and new treatment approaches, cancer corresponds to the second leading cause of death worldwide (Fitzmaurice et al, 2015). CBS, CSE, and MpST catalyze the cyst(e)ine-dependent production of cysteine persulfide (CysSSH), which in several (patho)physiological contexts affords protection from damaging cysteine oxidation (e.g., Filipovic et al, 2018; Zivanovic et al, 2019; Zuhra et al, 2021). Another recently proposed pathway linking cysteine catabolism with mitochondrial bioenergetics concerns the mitochondrial isoform of cysteinyl-tRNA synthase (CARS2), which converts cysteine into CysSSH and incorporates persulfidated cysteine into nascent polypeptides (Akaike et al, 2017; Bianco et al, 2019). XCT has been implicated as part of highly favorable metabolic cancer phenotype, presenting increased capacity of ATP generation amongst other features pivotal for cancer cells survival and chemoresistance (Polewski et al, 2016; Jourdain et al, 2021)
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