2. Academic Validation
  3. Arsenic trioxide sensitizes pancreatic cancer cells to gemcitabine through downregulation of the TIMP1/PI3K/AKT/mTOR axis

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

  • Transl Res. 2023 May:255:66-76. doi: 10.1016/j.trsl.2022.11.007.
Zhenfeng Tian 1,  Ying Tan 2,  Xingyi Lin 1,  Mingxin Su 1,  Lele Pan 1,  Lijun Lin 3,  Guangsheng Ou 4,  Yinting Chen 5
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China.
  • 4 Department of Gastrointestinal Surgery, The Third-Affiliated Hospital of Sun Yat-Sen University, Guangzhou, P.R. China. Electronic address: [email protected].
  • 5 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. Electronic address: [email protected].
PMID: 36400307 DOI: 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.

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