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Transcription factor p8 regulates autophagy in response to disulfiram via PI3K/mTOR/p70S6K signaling pathway in pancreatic cancer cells

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Abstract

Disulfiram (DSF), which is an inhibitor of aldehyde dehydrogenase (ALDH) and approved by the FDA for the treatment of alcoholism previously, has been repurposed for use as a cancer treatment because of its potent effect in preclinical studies. In this study, we found that disulfiram forms potent complexes with copper (DSF/Cu) inhibited cell proliferation, induced apoptosis in human pancreatic cancer cells, which was detected by flow cytometry and western blotting. Meanwhile, autophagy and autophagic flux also clearly observed by transmission electron microscopy, confocal microscopy and flow cytometry. Our results also showed that DSF/Cu induced transcription factor p8 upregulation and PI3K/mTOR signaling pathway activation detected by real-time PCR and western blotting. Additionally, suppression of p8 inactivated the mTOR signaling pathway and autophagic flux maintained. Furthermore, mechanism study indicated that autophagy induced by DSF/Cu was regulated by p8 and was related to PI3K/mTOR/p70S6K signaling pathway in pancreatic cancer cells. Our findings provide insights into the role of p8 in regulating autophagy induced by DSF/Cu effects in pancreatic cancer cells.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81872426, X. Z.) and Natural Science Foundation of Jiangsu Province, China (BK20181372, X.Z.).

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  1. Zhangyu Yao and Xiang Li contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Antibody Technology, National Health Commission, Nanjing Medical University, 101 Longmian Road, Nanjing, 211166, Jiangsu, China

    Zhangyu Yao, Xiang Li, Jun Gao, Yutao Wang, Linmei Xiao, Xinxia Chang, Zhenqing Feng & Xiao Zhang

  2. Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing Medical University, 101 Longmian Road, Nanjing, 211166, Jiangsu, China

    Zhangyu Yao, Xiang Li, Jun Gao, Yutao Wang, Linmei Xiao, Xinxia Chang, Zhenqing Feng & Xiao Zhang

  3. Department of Head and Neck Surgery, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, 42 Baiziting Street, Nanjing, 210009, Jiangsu, China

    Zhangyu Yao & Fangzhou Liu

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  1. Zhangyu Yao
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Yao, Z., Li, X., Gao, J. et al. Transcription factor p8 regulates autophagy in response to disulfiram via PI3K/mTOR/p70S6K signaling pathway in pancreatic cancer cells. Human Cell 35, 1464–1474 (2022). https://doi.org/10.1007/s13577-022-00731-3

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