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

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.

Long non‑coding RNA nuclear paraspeckle assembly transcript 1 regulates ionizing radiation‑induced pyroptosis via microRNA‑448/gasdermin E in colorectal cancer cells

“…The N domains of the gasdermin family with the exception of DFNB59 are capable of inducing pyroptosis (3,5). In particular, GSDME is cleaved by caspase-3 (Casp3) and switches apoptosis to pyroptosis in several cancers, which is associated with the side effects of chemotherapy and antitumor immunity (6) in breast cancer (7), lung cancer (8), gastric cancer (9) and colorectal cancer (10). Growing evidence suggests that numerous chemotherapeutic drugs, such as cisplatin and etoposide (6), may activate pyroptosis via canonical or noncanonical inflammasome pathways, including TLR and MAPK pathways (11), inhibit cancer progression Long non-coding RNA nuclear paraspeckle assembly transcript 1 regulates ionizing radiation-induced pyroptosis via microRNA-448/gasdermin E in colorectal cancer cells and overcome apoptosis resistance, which are major causes of cancer resistance (12).…”

Targeting Reactive Oxygen Species Capacity of Tumor Cells with Repurposed Drug as an Anticancer Therapy

“…At moderate concentrations, ROS have been implicated in tumor initiation and progression, malignant conversion, and resistance to chemotherapy. The higher concentrations of ROS result in damage cellular biomolecules and cause gene mutations, thus promoting canceration of normal cells or inducing cancer cell apoptosis, necrosis, autophagy, ferroptosis, and pyroptosis [ 48 , 86 ] ( Figure 5 ). Therefore, the roles of ROS are complicated, and ROS operate as a diversified biochemical entity in cancer progression.…”

Pyroptosis: A promising therapeutic target for noninfectious diseases

“…Since GSDMA and GSDME exert critical tumour‐suppressive effects on tumorigenesis, upregulation of GSDMA/GSDME and induction of GSDMA/GSDME‐related pyroptosis might be a promising therapeutic target for the treatment of cancer. Chemotherapeutics, such as doxorubicin, lobaplatin, cisplatin and tetraarsenic hexoxide, can suppress the growth of neuroblastoma, melanoma, colon cancer cells and breast cancer by inducing GSDME‐mediated pyroptosis 85–88 . Recently, Zhang et al 33 showed that intratumoral injection of DM‐αKG can notably repress tumour growth and metastasis through caspase‐8‐GSDMC‐mediated pyroptosis.…”

“…Chemotherapeutics, such as doxorubicin, lobaplatin, cisplatin and tetraarsenic hexoxide, can suppress the growth of neuroblastoma, melanoma, colon cancer cells and breast cancer by inducing GSDME‐mediated pyroptosis. 85 , 86 , 87 , 88 Recently, Zhang et al 33 showed that intratumoral injection of DM‐αKG can notably repress tumour growth and metastasis through caspase‐8‐GSDMC‐mediated pyroptosis. Moreover, GSDME/GSDMB‐dependent pyroptosis is implicated in cytotoxic T lymphocytes or chimeric antigen receptor (CAR) T cell‐mediated antitumour immunity.…”