Polysulfides and thioredoxin antagonistically regulate caspase persulfidation and cancer cell apoptosis

Hydrogen sulfide (H2S) has emerged as a signaling molecule involved in various physiological and pathological processes. H2S acts in part by modifying cysteine residues on target proteins via a posttranslational modification known as persulfidation. In the present study, using a combination of in vitro and cellular assays, we investigated the apoptosis-modulating effects of polysulfides, oxidation products of H2S .

We found that organic or synthetic polysulfides strongly and rapidly inhibited the enzymatic activity of caspase-3, a major apoptotic executioner protease. In apoptotically stimulated HeLa cells, short-term exposure to polysulfides triggered caspase-3 and caspase-9 persulfidation and deactivation. These effects were antagonized by the thioredoxin/thioredoxin reductase system (Trx/TrxR). Indeed, Trx/TrxR restored the activity of polysulfide-inactivated caspase-3 in vitro, and inhibition of TrxR potentiated polysulfide-mediated suppression of caspase-9 activity in situ. Moreover, under conditions of low TrxR activity, early cell exposure to polysulfides lead to enhanced persulfidation of initiator caspase-9, resulting in decreased apoptosis. Finally, we provide evidence that procaspase-9 is endogenously persulfidated in resting cells and undergoes depersulfidation during its apoptotic activation.

Taken together, our results reveal that polysulfides target the caspase-9/3 cascade to suppress cancer cell apoptosis. The findings further suggest that Trx/TrxR-mediated depersulfidation may regulate caspase-dependent cell death.