The degree of caspase-3 aggregation determines the selectivity of arsenic-induced cell death.

It is well known that apoptosis is triggered by arsenic. Meanwhile, recent evidence has demonstrated that arsenic also induces a non-canonical form of regulated cell death (RCD) called parthanatos that is triggered by the overactivation of poly (ADP-ribose) polymerase-1 (PARP-1). Here, we provide evidence of a novel mechanistic link between parthanatos and apoptosis induced by arsenic. Exposure to sodium arsenite clearly induced parthanatos in typical cancer cell lines such as HeLa and HT1080 cells, without activation of the apoptotic cascade, including the caspase-3 activation. Of note, we observed aggregation of caspase-3 in response to sodium arsenite, which was abolished by treatment with 4-phenylbutyrate (4-PBA), a chemical chaperone that prevents protein aggregation. Interestingly, in the presence of 4-PBA, sodium arsenite induced apoptosis rather than parthanatos. These findings suggest that the disaggregation of caspase-3 allows arsenic to induce the caspase-3 activation, and subsequent apoptosis. Thus, our results show that the degree of the caspase-3 aggregation may be a critical determinant of the selectivity of sodium arsenite-induced cell death.