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

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Abstract

Induction of cancer cell death is an established treatment strategy, but chemotherapy drug-mediated apoptosis can be evaded by many tumors. Pyroptosis is a type of inflammatory programmed cell death (PCD) that is important for organism immunity. Tubeimoside-I (TBMS1) is a plant-derived component that exhibits antitumor activity. However, it is unclear how TBMS1 induces pyroptosis to inhibit colorectal cancer (CRC). In this study, we demonstrated that TBMS1 is able to induce pyroptosis in murine CRC cells and releases pro-inflammatory cytokines. Mechanistically, we found that TBMS1 inhibits CRC cell proliferation and migration and induces pyroptosis by activating caspase-3 and cleaving gasdermin E (GSDME) through the inhibition of PKM2. In the animal experiments, 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 inhibited M2-type polarization by blocking STAT6 pathway activation in RAW 264.7 cells. To sum up, our findings suggest that TBMS1 triggers pyroptosis in CRC by acting on the PKM2/caspase-3/GSDME signaling pathway. Additionally, it modulates the antitumor immune response in CRC murine models. This study provides a promising basis for the potential use of TBMS1 in treating CRC.

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Data availability

The data that support the findings of this study are available from the corresponding authors, upon reasonable request.

Abbreviations

CRC:

Colorectal cancer

CRS:

Cytoreductive surgery

PCD:

Programmed cell death

PKM2:

Pyruvate kinase M2

TBMS1:

Tubeimoside-1

GSDME:

Gasdermin E

FBS:

Fetal bovine serum

DMSO:

Dimethyl sulfoxide

DMEM:

Dulbecco’s modified Eagle’s medium

CCK-8:

Counting Kit-8

ELISA:

Enzyme-linked immunosorbent assay

ARG1:

Arginase 1

IL-10:

Interleukin 10

IL-4:

Interleukin 4

IL-18:

Interleukin 18

IL-1β:

Interleukin 1 β

IFN-γ:

Interferon γ

IC50 :

Half maximal inhibitory concentration

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Funding

This research was supported by the National Natural Science Foundation of China (no. 81971858), the Inner Mongolia Natural Science Foundation (no. 2022MS08029), the National Natural Science Foundation of Tianjin (no. 18JCQNJC13400; no.19JCZDJC36200), and the science foundation of Tianjin Municipal Health Bureau (no. 2021009; no. 2021044; no. 2021097).

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Author notes

  1. Dongsheng Hu and Lingzhi Cui contributed equally to this article.

Authors and Affiliations

  1. Graduate School, Tianjin Medical University, Tianjin, China

    Dongsheng Hu, Lingzhi Cui, Sijia Zhang, Siqi He & Ximo Wang

  2. Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin Nankai Hospital, Tianjin, China

    Yuzhen Zhuo, Dihua Li, Lanqiu Zhang, Yanli Wang, Lei Yang & Ximo Wang

  3. Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Integrative Medicine for Acute Abdominal Diseases, Tianjin University, Tianjin, China

    Ximo Wang

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  1. Dongsheng Hu
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Contributions

All the authors have made important contributions to this work and agreed to the final version. Lei Yang and Ximo Wang designed the study. Dongsheng Hu and Lingzhi Cui wrote the original draft and conducted animal experiments. Sijia Zhang, Yuzhen Zhuo and Siqi He conducted cell experiments and data analysis. In addition, Dihua Li, Lanqiu Zhang and Yanli Wang carried out molecular docking, project management and supervision. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding authors

Correspondence to Lei Yang or Ximo Wang.

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Ethical approval

The animal study was reviewed and approved by the Animal Ethics and Welfare Committee of Tianjin Nankai Hospital (No. NKYY-DWLL-2021-097).

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The authors declare no competing interests.

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Hu, D., Cui, L., Zhang, S. et al. Antitumor effect of tubeimoside-I on murine colorectal cancers through PKM2-dependent pyroptosis and immunomodulation. Naunyn-Schmiedeberg's Arch Pharmacol (2023). https://doi.org/10.1007/s00210-023-02855-1

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