Int J Biol Sci 2022; 18(2):717-730. doi:10.7150/ijbs.64350 This issue

Research Paper

Apoptin induces pyroptosis of colorectal cancer cells via the GSDME-dependent pathway

Zirui Liu1,2, Yiquan Li3, Yilong Zhu3, Nan Li2, Wenjie Li2, Chao Shang2, Gaojie Song2, Shanzhi Li2, Jianan Cong2, Tingyu Li2, Zhiru Xiu2, Jing Lu2, Chenchen Ge2, Xia Yang2, Yaru Li2, Lili Sun2,5✉, Xiao Li2,3,4✉, Ningyi Jin1,2,3,4✉

1. College of Veterinary Medicine, Jilin University, Changchun, 130062, China.
2. Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 130122, China.
3. Academician Workstation of Jilin Province, Changchun University of Chinese Medicine, Changchun, 130021, China.
4. Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, China.
5. Department of Head and Neck Surgery, Tumor Hospital of Jilin Province, Changchun, 130012, China.

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Citation:
Liu Z, Li Y, Zhu Y, Li N, Li W, Shang C, Song G, Li S, Cong J, Li T, Xiu Z, Lu J, Ge C, Yang X, Li Y, Sun L, Li X, Jin N. Apoptin induces pyroptosis of colorectal cancer cells via the GSDME-dependent pathway. Int J Biol Sci 2022; 18(2):717-730. doi:10.7150/ijbs.64350. Available from https://www.ijbs.com/v18p0717.htm

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Abstract

Graphic abstract

Apoptin is a small molecular weight protein encoded by the VP3 gene of chicken anemia virus (CAV). It can induce apoptosis of tumor cells and play anti-tumorigenic functions. In this study, we identified a time-dependent inhibitory role of apoptin on the viability of HCT116 cells. We also demonstrated that apoptin induces pyroptosis through cleaved caspase 3, and with a concomitant cleavage of gasdermin E (GSDME) rather than GSDMD. GSDME knockdown switched the apoptin-induced cell death from pyroptosis to apoptosis in vitro. Furthermore, we demonstrated that the effect of apoptin on GSDME-dependent pyroptosis could be mitigated by caspase-3 and caspase-9 siRNA knockdown. Additionally, apoptin enhanced the intracellular reactive oxygen species (ROS), causing aggregation of the mitochondrial membrane protein Tom20. Moreover, bax and cytochrome c were released to the activating caspase-9, eventually triggering pyroptosis. Therefore, GSDME mediates the apoptin-induced pyroptosis through the mitochondrial apoptotic pathway. Finally, using nude mice xenografted with HCT116 cells, we found that apoptin induces pyroptosis and significantly inhibits tumor growth. Based on this mechanism, apoptin may provide a new strategy for colorectal cancer therapy.