Small molecule inhibitor against onco-mucins disrupts Src/FosL1 axis to enhance gemcitabine efficacy in pancreatic ductal adenocarcinoma.

Autor: Zhang C; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Department of Surgical Oncology, University of Nebraska Medical Center, Omaha, NE, USA., Atri P; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Nallasamy P; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Parte S; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Rauth S; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Nimmakayala RK; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Marimuthu S; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Chirravuri-Venkata R; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Bhatia R; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Halder S; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Shah A; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Cox JL; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA., Smith L; Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE, USA., Kumar S; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Foster JM; Department of Surgical Oncology, University of Nebraska Medical Center, Omaha, NE, USA., Kukreja RC; Division of Cardiology, Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, 23298-0204, USA., Seshacharyulu P; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Ponnusamy MP; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Disease, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: mpalanim@unmc.edu., Batra SK; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Fred and Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer and Allied Disease, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: sbatra@unmc.edu.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2022 Dec 28; Vol. 551, pp. 215922. Date of Electronic Publication: 2022 Sep 19.
DOI: 10.1016/j.canlet.2022.215922
Abstrakt: Mucin MUC4 is an aberrantly expressed oncogene in pancreatic ductal adenocarcinoma (PDAC), yet no pharmacological inhibitors have been identified to target MUC4. Here, we adapted an in silico screening method using the Cancer Therapeutic Response Database (CTRD) to Identify Small Molecule Inhibitors against Mucins (SMIMs). We identified Bosutinib as a candidate drug to target oncogenic mucins among 126 FDA-approved drugs from CTRD screening. Functionally, Bosutinib treatment alone/and in combination with gemcitabine (Gem)/5' fluorouracil (5FU) reduced in vitro viability, migration, and colony formation in multiple PDAC cell lines as well as human PDAC organoid prolifertaion and growth and in vivo xenograft growth. Further, biochemical and molecular analyses showed that Bosutinib exhibited these functional effects by downregulating MUC4 mucin at both transcript and translation levels in a dose- and time-dependent manner. Mechanistically, global transcriptome analysis in PDAC cells upon treatment with Bosutinib revealed disruption of the Src-ERK/AKT-FosL1 pathway, leading to decreased expression of MUC4 and MUC5AC mucins. Taken together, Bosutinib is a promising, novel, and highly potent SMIMs to target MUC4/MUC5AC mucins. This mucin-targeting effect of Bosutinib can be exploited in the future with cytotoxic agents to treat mucinous tumors.
Competing Interests: Declaration of competing interest SKB is a founding member of Sanguine Diagnostics and Therapeutics, Inc. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: