Antitumor effect of tubeimoside-I on murine colorectal cancers through PKM2-dependent pyroptosis and immunomodulation

Abstract

Abstract Induction of cancer cell death is a well-established treatment strategy, but many tumors can escape chemotherapy drug-mediated apoptosis. Pyroptosis is a kind of new inflammatory programmed cell death (PCD), which is crucial for immunity of the organism. Tubeimoside- I (TBMS1) is a plant-derived component with antitumor activity. However, the mechanism by which TBMS1 induces pyroptosis to inhibit colorectal cancer (CRC) remains unclear. In this study, we demonstrated that TBMS1 is able to induce pyroptosis in murine CRC cells, and releases pro-inflammatory cytokines. Mechanistically, we identified that TBMS1 inhibits cell migration and induces pyroptosis through activation of caspase-3, and cleavage of gasdermin E (GSDME) by inhibiting PKM2. Meanwhile, TBMS1 attenuated the weight of solid tumors, increased the proportion of CD8+ cytotoxic T cells, and reduced the content of M2 type macrophages in the spleen of tumor-bearing mice. Furthermore, TBMS1 restrained M2-like polarization by inhibiting the activation of Stat6 signal pathway in the RAW 264.7 cells. In conclusion, our results indicated that TBMS1 induces pyroptosis in CRC by targeting PKM2/caspase-3/GSDME signal axis and also regulates antitumor immunity in CRC. This study lays a potential theoretical foundation for the clinical application of TBMS1 in the treatment of CRC.