Cyclic pentapeptide cRGDfK enhances the inhibitory effect of sunitinib on TGF-β1-induced epithelial-to-mesenchymal transition in human non-small cell lung cancer cells.

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  • Author(s): Park KY;Park KY; Kim J; Kim J
  • Source:
    PloS one [PLoS One] 2020 Aug 18; Vol. 15 (8), pp. e0232917. Date of Electronic Publication: 2020 Aug 18 (Print Publication: 2020).
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
    • Publication Information:
      Original Publication: San Francisco, CA : Public Library of Science
    • Subject Terms:
      Carcinoma, Non-Small-Cell Lung/*drug therapy ; Epithelial-Mesenchymal Transition/*drug effects ; Lung Neoplasms/*drug therapy ; Peptides, Cyclic/*administration & dosage ; Sunitinib/*administration & dosage ; Transforming Growth Factor beta1/*antagonists & inhibitors; A549 Cells ; Adenosine Triphosphate/metabolism ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Carcinoma, Non-Small-Cell Lung/metabolism ; Carcinoma, Non-Small-Cell Lung/pathology ; Catalytic Domain ; Cell Line, Tumor ; Cell Survival/drug effects ; Drug Synergism ; Epithelial-Mesenchymal Transition/genetics ; Epithelial-Mesenchymal Transition/physiology ; Humans ; Integrin alphaVbeta3/antagonists & inhibitors ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Molecular Docking Simulation ; Neoplasm Invasiveness/pathology ; Neoplasm Invasiveness/prevention & control ; Protein Serine-Threonine Kinases/antagonists & inhibitors ; Protein Serine-Threonine Kinases/chemistry ; Protein Serine-Threonine Kinases/metabolism ; Smad Proteins/metabolism ; Wnt Signaling Pathway/drug effects
    • Abstract:
      In human lung cancer progression, the EMT process is characterized by the transformation of cancer cells into invasive forms that migrate to other organs. Targeting to EMT-related molecules is emerging as a novel therapeutic approach for the prevention of lung cancer cell migration and invasion. Traf2- and Nck-interacting kinase (TNIK) has recently been considered as an anti-proliferative target molecule to regulate the Wnt signaling pathway in several types of cancer cells. In the present study, we evaluated the inhibitory effect of a tyrosine kinase inhibitor sunitinib and the integrin-αⅤβ3 targeted cyclic peptide (cRGDfK) on EMT in human lung cancer cells. Sunitinib strongly inhibited the TGF-β1-activated EMT through suppression of Wnt signaling, Smad and non-Smad signaling pathways. In addition, the cRGDfK also inhibited the expression of TGFβ1-induced mesenchymal marker genes and proteins. The anti-EMT effect of sunitinib was enhanced when cRGDfK was treated together. When sunitinib was treated with cRGDfK, the mRNA and protein expression levels of mesenchymal markers were decreased compared to the treatment with sunitinib alone. Co-treatment of cRGDfK has shown the potential to improve the efficacy of anticancer agents in combination with therapeutic agents that may be toxic at high concentrations. These results provide new and improved therapies for treating and preventing EMT-related disorders, such as lung fibrosis and cancer metastasis, and relapse.
      Competing Interests: Author K.Y. Park was employed by the company CHA Meditech Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing and materials.
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    • Accession Number:
      0 (Biomarkers, Tumor)
      0 (Integrin alphaVbeta3)
      0 (Peptides, Cyclic)
      0 (Smad Proteins)
      0 (TGFB1 protein, human)
      0 (Transforming Growth Factor beta1)
      0 (cyclic (arginyl-glycyl-aspartyl-phenylalanyl-lysyl))
      8L70Q75FXE (Adenosine Triphosphate)
      EC 2.7.11.1 (Protein Serine-Threonine Kinases)
      EC 2.7.11.1 (TNIK protein, human)
      V99T50803M (Sunitinib)
    • Publication Date:
      Date Created: 20200819 Date Completed: 20201001 Latest Revision: 20211204
    • Publication Date:
      20240105
    • Accession Number:
      PMC7433881
    • Accession Number:
      10.1371/journal.pone.0232917
    • Accession Number:
      32810161