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Aims: Current treatment options for ovarian clear cell carcinoma (OCCC) are limited to combination of platinum-based and other cytotoxic agents to which patients respond poorly due to intrinsic chemoresistance. There is therefore an urgent need to develop alternative therapeutic strategies for OCCC. Results: Cysteine deprivation suppresses OCCC growth in vitro and in vivo with no apparent toxicity. Modes of cell death induced by cysteine deprivation in OCCC are determined by their innate metabolic profiles. Cysteine-deprived glycolytic OCCC is abolished primarily by oxidative stress-dependent necrosis and ferroptosis, which can otherwise be prevented by pretreatment with antioxidative agents. Meanwhile, OCCC that relies on mitochondria respiration for its bioenergetics is suppressed through apoptosis, which can otherwise be averted by pretreatment with cysteine precursor alone, but not with antioxidative agents. Cysteine deprivation induces apoptosis in respiring OCCC by limiting iron-sulfur (Fe-S) cluster synthesis in the mitochondria, without which electron transport chain may be disrupted. Respiring OCCC responds to Fe-S cluster deficit by increasing iron influx into the mitochondria, which leads to iron overload, mitochondria damage, and eventual cell death. Innovation/Conclusion: This study demonstrates the importance of cysteine availability in OCCC that is for its antioxidative property and its less appreciated role in mitochondria respiration. Regardless of OCCC metabolic profiles, cysteine deprivation abolishes both glycolytic and respiring OCCC growth in vitro and in vivo . Conclusion: This study highlights the therapeutic potential of cysteine deprivation for OCCC.

Retina is one of the tissues that exposed to highest oxidative stress due to its high metabolic rate, abundant photosensitizing activity and visible light exposure. With these high chances of oxidative damage, antioxidative capacity of retinal tissues is essential for maintaining the proper functions of retina. Cytoprotective roles of hydrogen sulfide (H2S) have been documented and were largely attributed to its antioxidative activity. However, whether are these three H2S-producing enzymes (cystathionine-gamma-lyase (CSE), cystathionine-beta-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MPST) plays antioxidative roles in retinal tissue is unclear. In this study, we examined the role of CSE, CBS and MPST enzymes in human retinal pigmented epithelial cell line ARPE19. ARPE19 expressed comparatively similar protein levels of the three enzymes. Surprisingly, gene silencing of CSE sensitized the cells to hydrogen peroxide (H2O2) challenge to a much greater extent as compared to gene silencing in CBS or MPST. We also observed that loss of CSE in ARPE19 resulted in decreased level of glutathione, higher oxidative stress and accelerated senescence. Taken together, our data suggest that CSE is essential for retinal functions by maintaining its redox balance. [ABSTRACT FROM AUTHOR]