Miltirone induces GSDME-dependent pyroptosis in colorectal cancer by activating caspase 3
Guangwei Zheng,
Zhipeng Fang,
Zhenlv Lin,
Guoxian Guan
Affiliations
Guangwei Zheng
Department of Emergency Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China; Department of Emergency Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
Zhipeng Fang
Department of Emergency Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China; Department of Emergency Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
Zhenlv Lin
Department of Emergency Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China; Department of Emergency Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China
Guoxian Guan
Department of Colorectal Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China; Department of Colorectal Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China; Corresponding author. Department of Colorectal Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
Colorectal cancer (CRC) is a common and malignant tumor, ranking as the third most common cancer in men and the second most common cancer in women. Pyroptosis, a recently described programmed cell death mechanism mediated by the GSDM family, has emerged as an immunogenic mechanism for chemotherapy drugs in tumor treatment. In this study, we discovered that Miltirone has the ability to reduce the viability of CRC cells (SW620 and HCT116) and cause the proteolytic cleavage of gasdermin E (GSDME) in CRC cells. It was also observed that inhibiting GSDME prevented pyroptotic cell death induced by Miltirone in SW620 and HCT116 cells. Furthermore, the main active component of Miltirone was found to effectively bind with caspase 3. SiRNA-mediated caspase 3 silencing and specific caspase 3 inhibitor Z-DEVD-FMK were shown to weaken Miltirone-induced GSDME-dependent cell death. The findings of the study suggest that Miltirone has the potential to inhibit the growth of CRC tumors in vivo by inducing pyroptotic cell death. This indicates that Miltirone could be a viable therapeutic agent for the treatment of CRC through GSDME-dependent pyroptosis. These results offer a promising new option for the clinical treatment of CRC.
