Abstract 989: Tetraarsenic hexoxide enhances generation of mitochondrial ROS to promote pyroptosis by inducing the activation of caspase-3/GSDME in triple-negative breast cancer cells

Abstract

Abstract Modified arsenic derivative compounds such as arsenic trioxide (As2O3), arsenic trisulfide (As2S3), and tetraarsenic hexoxide (As4O6) have been known to be one of the potent anti-cytotoxic effects in various cancer cells, including leukemia, glioma, colon, breast, and cervix cancer cells. Particularly, tetraarsenic hexoxide was developed as a chemotherapeutic agent for patients with advanced cancers. Although anti-cancer effect of tetraarsenic hexoxide has been extensively studied in various cancer cells, the molecular basis of its tumor inhibitory activity remains poorly understood. In this study, we suggest a mechanism of tetraarsenic hexoxide induces pyroptosis through the increase of mitochondrial ROS by targeting phosphorylation of mitochondrial STAT3, subsequently activating caspase-3/GSDME that eventually leads to suppression of cancer progression of TNBC cells. Interestingly, we first found that tetraarsenic hexoxide markedly induced pyroptotic cell death through caspase-3 in releading N-terminal fragments of GSDME in TNBC cells. Indeed, tetraarsenic hexoxide-treated TNBC cells exhibited pyroptotic cell death and the release of LDH. Supporting this observation, inhibition of active caspase-3 attenuated tetraarsenic hexoxide-induced pyroptotic features by blocking the cleavage of GSDME. In conclusion, our results suggest a mechanism of tetraarsenic hexoxide by inducing pyroptosis through the increase of mitochondrial ROS by targeting phosphorylation of mitochondrial STAT3, subsequently activating caspase-3/GSDME that eventually leads to suppression of cancer progression of TNBC cells. Also, given that traditional chemotherapeutic agents, tetraarsenic hexoxide may be useful for aggressive TNBC cells showing resistance to apoptosis as a new GSDME-targeted therapeutic strategy. Citation Format: Haein An, Jin Sun Heo, Akira Ooshima, Zhaoyan Wu, Seong-Jin Kim, ILLJU BAE, Kyung-Min Yang. Tetraarsenic hexoxide enhances generation of mitochondrial ROS to promote pyroptosis by inducing the activation of caspase-3/GSDME in triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 989.