Cleavage of GSDME by caspase-3 determines lobaplatin-induced pyroptosis in colon cancer cells

• Published in: Cell death & disease 2019-02, Vol.10 (3), p.193-193, Article 193
• Main Authors: Yu, Junhui, Li, Shan, Qi, Jie, Chen, Zilu, Wu, Yunhua, Guo, Jing, Wang, Kai, Sun, Xuejun, Zheng, Jianbao
• Format: Article
• Language: English
• Subjects: 13/109; 13/2; 13/31; 13/89; 14; 14/28; 14/63; 38; 42; 59; 631/67/1059/99; 631/67/1504/1885/1393; 64; 82; 82/80; Animals; Antibodies; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Biochemistry; Biomedical and Life Sciences; Caco-2 Cells; Caspase; Caspase 3 - metabolism; Caspase-3; Cell Biology; Cell Culture; Cell death; Cell size; Cell Survival; Colon cancer; Colonic Neoplasms - enzymology; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colonic Neoplasms - ultrastructure; Colorectal cancer; Colorectal carcinoma; Cyclobutanes - pharmacology; Cytochrome c; Cytochromes c - metabolism; Cytosol; HCT116 Cells; HT29 Cells; Humans; Immunology; Innate immunity; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Life Sciences; MAP Kinase Kinase 4 - genetics; MAP Kinase Kinase 4 - metabolism; Mice; Mice, Inbred BALB C; Mice, Nude; Mitochondria; Mitochondria - metabolism; Organoplatinum Compounds - pharmacology; Phosphate-Binding Proteins - genetics; Phosphate-Binding Proteins - metabolism; Phosphorylation; Pyroptosis; Pyroptosis - drug effects; Pyroptosis - genetics; Reactive oxygen species; Reactive Oxygen Species - metabolism; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; RNA, Small Interfering - genetics; Signal Transduction - genetics; Transmission electron microscopy; Transplantation, Heterologous; Tumors
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-1441-4

Pyroptosis, a form of programmed cell death (PCD), has garnered increasing attention as it relates to innate immunity and diseases. However, the involvement of pyroptosis in the mechanism by which lobaplatin acts against colorectal cancer (CRC) is unclear. Our study revealed that treatment with lobaplatin reduced the viability of HT-29 and HCT116 cells in a dose-dependent manner. Morphologically, HT-29 and HCT116 cells treated with lobaplatin exhibited microscopic features of cell swelling and large bubbles emerging from the plasma membrane, and transmission electron microscopy (TEM) revealed multiple pores in the membrane. GSDME, rather than GSDMD, was cleaved in lobaplatin-induced pyroptosis in HT-29 and HCT116 cells due to caspase-3 activation. Knocking out GSDME switched lobaplatin-induced cell death from pyroptosis to apoptosis but did not affect lobaplatin-mediated inhibition of growth and tumour formation of HT-29 and HCT116 cells in vivo and in vitro. Further investigation indicates that lobaplatin induced reactive oxygen species (ROS) elevation and JNK phosphorylation. NAC, a ROS scavenger, completely reversed the pyroptosis of lobaplatin-treated HT-29 and HCT116 and JNK phosphorylation. Activated JNK recruited Bax to mitochondria, and thereby stimulated cytochrome c release to cytosol, followed by caspase-3/-9 cleavage and pyroptosis induction. Therefore, in colon cancer cells, GSDME mediates lobaplatin-induced pyroptosis downstream of the ROS/JNK/Bax-mitochondrial apoptotic pathway and caspase-3/-9 activation. Our study indicated that GSDME-dependent pyroptosis is an unrecognized mechanism by which lobaplatin eradicates neoplastic cells, which may have important implications for the clinical application of anticancer therapeutics.