Cysteine deprivation targets ovarian clear cell carcinoma via oxidative stress and iron-sulfur cluster biogenesis deficit.

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 chemo-resistance. 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 is determined by their innate metabolic profiles. Cysteine-deprived glycolytic OCCC is abolished primarily by oxidative stress-dependent necrosis and ferroptosis that can otherwise be prevented by pre-treatment with anti-oxidative agents. Meanwhile, OCCC that relies on mitochondria respiration for its bioenergetics, is suppressed through apoptosis that can otherwise be averted by pre-treatment with cysteine precursor alone, but not with anti-oxidative 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 that 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 anti-oxidative 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. This study highlights the therapeutic potential of cysteine deprivation for OCCC.