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Arsenic trioxide sensitizes pancreatic cancer cells to gemcitabine through downregulation of the TIMP1/PI3K/AKT/mTOR axis

  • Author Footnotes
    † Zhenfeng Tian, Ying Tan, and Xingyi Lin contributed equally to this work.
    Zhenfeng Tian
    Footnotes
    † Zhenfeng Tian, Ying Tan, and Xingyi Lin contributed equally to this work.
    Affiliations
    Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China

    Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
    Search for articles by this author
  • Author Footnotes
    † Zhenfeng Tian, Ying Tan, and Xingyi Lin contributed equally to this work.
    Ying Tan
    Footnotes
    † Zhenfeng Tian, Ying Tan, and Xingyi Lin contributed equally to this work.
    Affiliations
    Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China

    Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China

    Department of Gastroenterology & Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China
    Search for articles by this author
  • Author Footnotes
    † Zhenfeng Tian, Ying Tan, and Xingyi Lin contributed equally to this work.
    Xingyi Lin
    Footnotes
    † Zhenfeng Tian, Ying Tan, and Xingyi Lin contributed equally to this work.
    Affiliations
    Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China

    Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
    Search for articles by this author
  • Mingxin Su
    Affiliations
    Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China

    Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
    Search for articles by this author
  • Lele Pan
    Affiliations
    Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China

    Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
    Search for articles by this author
  • Lijun Lin
    Affiliations
    Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
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  • Guangsheng Ou
    Correspondence
    Reprint requests: Department of Gastrointestinal Surgery, the third-affiliated hospital of Sun Yat-Sen University, Guangzhou 510600, P.R. China.
    Affiliations
    Department of Gastrointestinal Surgery, The Third-Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China
    Search for articles by this author
  • Yinting Chen
    Correspondence
    Reprint requests: Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou 510120, P.R. China
    Affiliations
    Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China

    Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
    Search for articles by this author
  • Author Footnotes
    † Zhenfeng Tian, Ying Tan, and Xingyi Lin contributed equally to this work.
Published:November 14, 2022DOI:https://doi.org/10.1016/j.trsl.2022.11.007

      Abstract

      Gemcitabine (GEM) is the first-line medication for pancreatic ductal adenocarcinoma (PDAC). However, over some treatment cycles, GEM sensitivity declines and chemotherapeutic resistance develops, resulting in tumor recurrence and metastasis. Therefore, it is critical to elucidate the mechanism of GEM chemoresistance. And a specific drug that is closely related to the mechanism is urgently required to sensitize GEM. Here, tissue inhibitor of matrix metalloproteinases 1 (TIMP1) and phosphorylated mammalian target of rapamycin (p-mTOR) were found to be substantially elevated in PDAC patients and were associated with worse overall survival. The TIMP1/PI3K/AKT/mTOR pathway was found in GEM-resistant PDAC cells and was revealed to be involved in epithelial-mesenchymal transition (EMT) and apoptosis. Furthermore, arsenic trioxide (ATO), a basic therapeutic drug for acute promyelocytic leukemia, mediated TIMP1 reduction by inducing reactive oxygen species generation and hampered the subsequent PI3K/AKT/mTOR axis. Moreover, the combination of ATO and GEM cooperatively suppressed the TIMP1/PI3K/AKT/mTOR pathway, synergistically inhibited EMT and promoted apoptosis. In vitro and in vivo, ATO combined with GEM has a collaborative anticancer effect, inhibiting cancer cell proliferation, migration, invasion, and suppressing tumor growth both in PDAC parental and GEM-resistant cells. Overall, the TIMP1/PI3K/AKT/mTOR pathway is present in PDAC and linked to GEM resistance. ATO suppresses the axis to sensitize GEM and reverse GEM resistance, suggesting a promising treatment for the disease.

      Abbreviations:

      ATO (Arsenic Trioxide), CI (Combined Index), DHE (Dihydroethidium), DMEM (Dulbecco's modified Eagle's medium), EMT (Epithelial-mesenchymal transition), GEM (Gemcitabine), HR (Hazard ratio), IHC (Immunohistochemistry), mTOR (Mammalian target of rapamycin), NAC (N-acetyl-L-cysteine), OS (Overall survival), PBS (Phosphate buffer solution), PDAC (Pancreatic ductal adenocarcinoma), p-mTOR (Phosphorylated mammalian target of rapamycin), qRT-PCR (Quantitative real time polymerase chainreaction), ROS (Reactive oxygen species), siRNA (Small interfering RNA), TIMP1 (Tissue inhibitor of matrix metalloproteinases 1)
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