Secretory Trefoil Factor 1 (TFF1) promotes gemcitabine resistance through chemokine receptor CXCR4 in Pancreatic Ductal Adenocarcinoma.

Autor: Shah A; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Jahan R; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Kisling SG; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Atri P; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Natarajan G; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Nallasamy P; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Cox JL; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-5900, USA., Macha MA; Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, Awantipora, Kashmir, India., Sheikh IA; King Fahd Medical Research Center, King Abdulaziz University, Jeddah, 21589, Saudi Arabia., Ponnusamy MP; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-5950, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, 68198-5950, USA., Kumar S; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA., Batra SK; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-5950, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, 68198-5950, USA. Electronic address: sbatra@unmc.edu.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2024 Aug 28; Vol. 598, pp. 217097. Date of Electronic Publication: 2024 Jul 02.
DOI: 10.1016/j.canlet.2024.217097
Abstrakt: Gemcitabine is the first-line treatment option for patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). However, the frequent adoption of resistance to gemcitabine by cancer cells poses a significant challenge in treating this aggressive disease. In this study, we focused on analyzing the role of trefoil factor 1 (TFF1) in gemcitabine resistance in PDAC. Analysis of PDAC TCGA and cell line datasets indicated an enrichment of TFF1 in the gemcitabine-resistant classical subtype and suggested an inverse correlation between TFF1 expression and sensitivity to gemcitabine treatment. The genetic ablation of TFF1 in PDAC cells enhanced their sensitivity to gemcitabine treatment in both in vitro and in vivo tumor xenografts. The biochemical studies revealed that TFF1 contributes to gemcitabine resistance through enhanced stemness, increasing migration ability of cancer cells, and induction of anti-apoptotic genes. We further pursued studies to predict possible receptors exerting TFF1-mediated gemcitabine resistance. Protein-protein docking investigations with BioLuminate software revealed that TFF1 binds to the chemokine receptor CXCR4, which was supported by real-time binding analysis of TFF1 and CXCR4 using SPR studies. The exogenous addition of TFF1 increased the proliferation and migration of PDAC cells through the pAkt/pERK axis, which was abrogated by treatment with a CXCR4-specific antagonist AMD3100. Overall, the present study demonstrates the contribution of the TFF1-CXCR4 axis in imparting gemcitabine resistance properties to PDAC cells.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SKB is one of the co-founders of Sanguine Diagnostics and Therapeutics, Inc. The other authors declare no potential conflicts of interest.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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