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

Haein An,Seong-Jin Kim,Kyung-Min Yang,Jin Sun Heo,Akira Ooshima,Jihee Lee,Kyung-Soon Park,Eunji Hong,Kyoungwha Pang,Pyunggang Kim,Zenglin Lian,Yuna Park,Hyeyeon Park,Illju Bae,Minjung Son,Siyoung Lee,Jinah Park,Zhaoyan Wu

doi:10.1038/s41419-021-03454-9

Abstract

Although tetraarsenic hexoxide is known to exert an anti-tumor effect by inducing apoptosis in various cancer cells, its effect on other forms of regulated cell death remains unclear. Here, we show that tetraarsenic hexoxide induces the pyroptotic cell death through activation of mitochondrial reactive oxygen species (ROS)-mediated caspase-3/gasdermin E (GSDME) pathway, thereby suppressing tumor growth and metastasis of triple-negative breast cancer (TNBC) cells. Interestingly, tetraarsenic hexoxide-treated TNBC cells exhibited specific pyroptotic characteristics, including cell swelling, balloon-like bubbling, and LDH releases through pore formation in the plasma membrane, eventually suppressing tumor formation and lung metastasis of TNBC cells. Mechanistically, tetraarsenic hexoxide markedly enhanced the production of mitochondrial ROS by inhibiting phosphorylation of mitochondrial STAT3, subsequently inducing caspase-3-dependent cleavage of GSDME, which consequently promoted pyroptotic cell death in TNBC cells. Collectively, our findings highlight tetraarsenic hexoxide-induced pyroptosis as a new therapeutic strategy that may inhibit cancer progression of TNBC cells.

Highlights

Triple-negative breast cancer (TNBC) accounts for 12 to 17% of patients with breast cancer worldwide, and frequently occurs in young African American women as well as women with BRCA1 mutations[1]
We found that tetraarsenic hexoxide induces typical pyroptotic characteristics, including balloon-like bubbling and release of lactate dehydrogenase (LDH) through pore formation in the plasma membrane in TNBC cells
We proposed a mechanism by which tetraarsenic hexoxide induced pyroptotic cell death via mitochondrial ROSmediated caspase-3/gasdermin E (GSDME) pathway by inhibiting phosphorylation of mitochondrial signal transducer and activator of transcription 3 (STAT3), thereby suppressing tumor growth and metastatic potential of aggressive TNBC cells (Fig. 7)

Summary

Introduction

Triple-negative breast cancer (TNBC) accounts for 12 to 17% of patients with breast cancer worldwide, and frequently occurs in young African American women as well as women with BRCA1 mutations[1]. Among the breast cancer subtypes, TNBC is highly heterogeneous and aggressive, resulting in the worst prognosis due to the Arsenic derivative compounds have been shown to exert anti-cancer effects. Studies have shown that modified arsenic derivative compounds such as arsenic trisulfide (As2S3) and tetraarsenic hexoxide (As4O6, TetraAS®) demonstrated potent anti-cytotoxic effect in various cancer cells, including leukemia, glioma, colon, breast, and cervix cancer cells[9,10,11,12,13]. It is reported that the inhibitory effect of tetraarsenic hexoxide on cell growth is more potent than that of arsenic trioxide in cervical cancer cells[15]. 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

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Conclusion