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Metformin Increases the Response of Cholangiocarcinoma Cells to Gemcitabine by Suppressing Pyruvate Kinase M2 to Activate Mitochondrial Apoptosis

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Abstract

Background

Cholangiocarcinoma (CCA) is a malignant tumor with a high mortality rate. Resistance to chemotherapy remains a major challenge related to cancer treatment, and increasing the sensitivity of cancer cells to therapeutic drugs is a major focus of cancer treatment.

Aims

We purposed to explore the role of Metformin in CCA involved in chemotherapeutic sensitivity and Pyruvate kinase M2 (PKM2) through regulating mitochondrial apoptosis in the present study.

Methods

CCA cell lines of HCC9810 and RBE were treated with Metformin companied with antagonists or agonists of PKM2, cells sensitivity to Gemcitabine, cell migration and invasion along with apoptosis, which is mediated by JC-1 and LDH were assayed.

Results

Our results indicated that Metformin and Gemcitabine exhibit synergistic effect on inhibition of cholangiocarcinoma cell viability, cell migration and invasion as well as promotion apoptosis of cholangiocarcinoma cells. In vivo, Metformin combined with Gemcitabine has cooperation in inhibiting the growth of cholangiocarcinoma cell-derived tumors. Moreover, Metformin and Gemcitabine inhibited expression of PKM2 and PDHB in HCC9810 and RBE.

Conclusion

Our study suggested that Metformin may increase the response of cholangiocarcinoma cells to Gemcitabine by suppressing PKM2 to activate mitochondrial apoptosis.

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Acknowledgments

This study was supported by Jiaxing Science and Technology Plan Project (No. 2018AY32044).

Funding

None.

Author information

Authors and Affiliations

  1. Department of General Surgery, Armed Police Coast Guard Corps Hospital, Jiaxing, Zhejiang, China

    Haishan Deng & Yongtao Zhang

  2. Jiaxing Shuguang Cosmetology Hospital, Jiaxing, Zhejiang, China

    Xiaomei Qian

  3. The Second Department of Biliary Duct, Eastern Hepatobiliary Surgery Hospital, Shanghai, China

    Wenlong Yu

  4. Department of Radiotherapy, The First Affiliated Hospital of Hainan Medical University, No. 31 Longhua Road, Haikou, 570102, Hainan, China

    Ping Yang

Authors
  1. Haishan Deng
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  2. Xiaomei Qian
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  3. Yongtao Zhang
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  4. Wenlong Yu
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  5. Ping Yang
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Contributions

HD: Conceptualization, Methodology. XQ: Data curation, Writing- Original draft preparation. YZ: Software, Writing- Reviewing and Editing. PY and WY: Conceptualization, Methodology.

Corresponding author

Correspondence to Ping Yang.

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All the authors declared that they have not any conflicts of interests.

Ethical approval

All the animal experiments were performed according to the animal ethics committee of Armed Police Coast Guard Corps Hospital with ethical approvement (202016).

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Deng, H., Qian, X., Zhang, Y. et al. Metformin Increases the Response of Cholangiocarcinoma Cells to Gemcitabine by Suppressing Pyruvate Kinase M2 to Activate Mitochondrial Apoptosis. Dig Dis Sci 69, 476–490 (2024). https://doi.org/10.1007/s10620-023-08210-x

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