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

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.

• Authors: Zirui Liu, Yiquan Li, Yilong Zhu, Nan Li, Wenjie Li, Chao Shang, Gaojie Song, Shanzhi Li, Jianan Cong, Tingyu Li, Zhiru Xiu, Jing Lu, Chenchen Ge, Xia Yang, Yaru Li, Lili Sun, Xiao Li, Ningyi Jin
• Journal: International journal of biological sciences (Int J Biol Sci) Vol. 18 Issue 2 Pg. 717-730 ( 2022) ISSN: 1449-2288 [Electronic] Australia
• PMID: 35002520 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• GSDME protein, human
• Pore Forming Cytotoxic Proteins
• Reactive Oxygen Species
• bcl-2-Associated X Protein
• Cytochromes c
• Caspase 3
• Caspase 9

Topics

• Animals
• Caspase 3 (genetics, metabolism)
• Caspase 9 (genetics, metabolism)
• Colorectal Neoplasms (metabolism, pathology)
• Cytochromes c (metabolism)
• Female
• HCT116 Cells
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mitochondria (metabolism)
• Pore Forming Cytotoxic Proteins (metabolism)
• Pyroptosis
• Reactive Oxygen Species (metabolism)
• Xenograft Model Antitumor Assays
• bcl-2-Associated X Protein (metabolism)