Coxsackievirus Group B3 Has Oncolytic Activity against Colon Cancer through Gasdermin E-Mediated Pyroptosis

Abstract

Colon cancer is the second leading cause of cancer-related death, and there are few effective therapies for colon cancer. This study explored the use of coxsackievirus group B3 (CVB3) as an oncolytic virus for the treatment of colon cancer. In this study, we verified that CVB3 induces death of colon cancer cell lines by directly observing cell morphology and Western blot results, and observed the oncolytic effects of CVB3 by constructing an immunodeficient nude mice model. Our data show that CVB3 induces pyroptosis in colon cancer cell lines. Mechanistically, we demonstrated that CVB3 causes cleavage of gasdermin E (GSDME), but not gasdermin D (GSDMD), by activating caspase-3. This leads to production of GSDME N-termini and the development of pores in the plasma membrane, inducing pyroptosis of colon cancer cell lines. We also demonstrate that CVB3-induced pyroptosis is promoted by reactive oxygen species (ROS). Finally, in vivo studies using immunodeficient nude mice revealed that intratumoral injection of CVB3 led to significant tumor regression. Our findings indicate that CVB3 has oncolytic activity in colon cancer cell lines via GSDME-mediated pyroptosis.

Co-expression patterns of cancer associated fibroblast markers reveal distinct subgroups related to patient survival in oropharyngeal squamous cell carcinoma

“…Within the CD8 high population, PDGFRb high status delineates patients with impaired survival. Previous reports describe elevated evasion of immune surveillance mediated by intratumoral transforming growth factor-beta (TGF-β) signaling, which is positively associated to PDGFRb expression ( Baba et al, 2022 ; Zhang Y. et al, 2022 ). In an analysis of metastatic urothelial cancer, a high TGF- β signature in fibroblasts attenuated response to PD-L1 blockade and contributed to CD8 T-cell exclusion ( Mariathasan et al, 2018 ).…”

Oncolytic virotherapy: basic principles, recent advances and future directions

“… 149 The oAds-armed apoptotic protein, encoded by the VP3 gene of chicken anemia virus (CAV), induces pyroptosis by cleaving caspase-3 and GSDME, and significantly inhibits the growth of colorectal tumors. 150 Other OVs, such as coxsackievirus B3, 151 HSV-1, 152 NDV, 153 etc., have also adopted the death mode, and these pyroptosis-based anticancer drugs may open up new possibilities for OV therapy in the future.…”

The multifaceted roles of GSDME-mediated pyroptosis in cancer: therapeutic strategies and persisting obstacles

“…Studies have demonstrated that GSDME-mediated pyroptosis is also essential to the development of colorectal cancer [ 119 ]. Coxsackievirus group B3 (CVB3) is able to induce pyroptosis in colon cancer cell lines both in vivo and in vitro [ 120 ]. Mechanistically, CVB3-induced pyroptosis is promoted by ROS, which activates the caspase-3/GSDME pathway to produce pores in the plasma membrane [ 120 ].…”

“…Coxsackievirus group B3 (CVB3) is able to induce pyroptosis in colon cancer cell lines both in vivo and in vitro [ 120 ]. Mechanistically, CVB3-induced pyroptosis is promoted by ROS, which activates the caspase-3/GSDME pathway to produce pores in the plasma membrane [ 120 ]. These findings suggest that CVB3 is effective in treating colon cancer through the GSDME-mediated pyroptosis pathway.…”