α‐NETA induces pyroptosis of epithelial ovarian cancer cells through the GSDMD/caspase‐4 pathway

Chemotherapy resistance is one of the most common causes of death among patients with ovarian cancer, and identifying novel antitumor agents is a priority. Here, we report that the novel molecule 2‐(anaphthoyl)ethyl‐trimethylammonium iodide (α‐NETA) induces epithelial ovarian cancer (EOC) cell pyroptosis through the gesdermin‐d (GSDMD)/caspase‐4 pathway. Furthermore, Cell Counting Kit‐8 fluorescence‐activated cell sorting analysis showed that α‐NETA treatment led to cell death in different ovarian cancer cell lines, including Ho8910, Ho8910PM, and A2780. Morphologic examination by electron microscopy indicated that cells treated with α‐NETA produced multiple microbubbles, typical of cells undergoing pyroptosis. α‐NETA also significantly increased expression of pyroptosis‐associated molecules including caspase‐4 and GSDMD in EOC cells. Knockdown of either caspase‐4 or GSDMD in ovarian cancer cells strongly interfered with α‐NETA cell‐killing activity, indicating that α‐NETA acts through the pyroptosis pathway. In vivo, α‐NETA treatment dramatically decreased the size of EOC tumors in mice. Our findings suggest that α‐NETA represents a potential new antitumor molecule or lead compound for EOC chemotherapy.—Qiao, L., Wu, X., Zhang, J., Liu, L., Sui, X., Zhang, R., Liu, W., Shen, F., Sun, Y., Xi, X. α‐NETA induces pyroptosis of epithelial ovarian cancer cells through the GSDMD/caspase‐4 pathway. FASEB J. 33, 12760–12767 (2019). www.fasebj.org