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Vesicle-associated membrane protein 8 knockdown exerts anti-proliferative, pro-apoptotic, anti-autophagic, and pro-ferroptotic effects on colorectal cancer cells by inhibition of the JAK/STAT3 pathway

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Abstract

Vesicle-associated membrane protein 8 (VAMP8), a soluble n-ethylmaleimide-sensitive factor receptor protein, acts as an oncogenic gene in the progression of several malignancies. Nevertheless, the roles and mechanisms of VAMP8 in colorectal cancer (CRC) progression remain unknown. The expression and prognostic significance of VAMP8 in CRC samples were analyzed through bioinformatics analyses. Cell proliferation was detected using CCK-8 and EdU incorporation assays and apoptosis was evaluated via flow cytometry. Western blot analysis was conducted to examine the protein expression. Ferroptosis was evaluated by measurement of iron metabolism, lipid peroxidation, and glutathione (GSH) content. VAMP8 was increased in CRC samples relative to normal samples on the basis of GEPIA and HPA databases. CRC patients with high level of VAMP8 had a worse overall survival. VAMP8 depletion led to a suppression of proliferation and promotion of apoptosis in CRC cells. Additionally, VAMP8 knockdown suppressed beclin1 expression and LC3-II/LC3-I ratio, elevated p62 expression, increased Fe2+, labile iron pool, lipid reactive oxygen species, and malondialdehyde levels, and repressed GSH content and glutathione peroxidase activity. Moreover, VAMP8 knockdown inhibited the activation of janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway in CRC cells. Mechanistically, activation of the JAK/STAT3 pathway by JAK1 or JAK2 overexpression attenuated VAMP8 silencing-mediated anti-proliferative, pro-apoptotic, anti-autophagic, and pro-ferroptotic effects on CRC cells. In conclusion, VAMP8 knockdown affects the proliferation, apoptosis, autophagy, and ferroptosis by the JAK/STAT3 pathway in CRC cells.

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Data are available from the corresponding author on reasonable request.

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Funding

This work was supported by Nanyang Basic and Frontier Research Project (No. JQYJ002) and Science and Technology Plan Project of Wolong District, Nanyang (No. KJ202314).

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Authors and Affiliations

  1. Department of General Surgery, Nanyang First People’s Hospital, Nanyang, China

    Yi Xu & Yan Tang

  2. Department of General Surgery, Tiantai People’s Hospital of Zhejiang Province, Taizhou, China

    Tianyao Yang

  3. Department of Thyroid and Breast Surgery, Nanyang First People’s Hospital, Nanyang, China

    Qiu Xu

  4. Nanyang Key Laboratory of Thyroid Tumor Prevention and Treatment, Nanyang First People’s Hospital, Nanyang, China

    Qiu Xu

  5. General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China

    Qiong Yang

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  4. Yan Tang
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Yi Xu and Tianyao Yang conducted the experiments. Qiu Xu and Yan Tang collected and analyzed the data. Qiong Yang designed the study and wrote the manuscript. All authors reviewed the manuscript.

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Yi Xu and Tianyao Yang are co-first authors.

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Xu, Y., Yang, T., Xu, Q. et al. Vesicle-associated membrane protein 8 knockdown exerts anti-proliferative, pro-apoptotic, anti-autophagic, and pro-ferroptotic effects on colorectal cancer cells by inhibition of the JAK/STAT3 pathway. J Bioenerg Biomembr (2024). https://doi.org/10.1007/s10863-024-10019-w

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