Bioinformatics and molecular insights to anti-metastasis activity of triethylene glycol derivatives

Vidhi Malik, Sukant Garg, Sajal Afzal, Jaspreet Kaur Dhanjal, Chae Ok Yun, Sunil C. Kaul, Durai Sundar, Renu Wadhwa

Research output: Contribution to journalArticle

Abstract

The anti-metastatic and anti-angiogenic activities of triethylene glycol derivatives have been reported. In this study, we investigated their molecular mechanism(s) using bioinformatics and experimental tools. By molecular dynamics analysis, we found that (i) triethylene glycol dimethacrylate (TD-10) and tetraethylene glycol dimethacrylate (TD-11) can act as inhibitors of the catalytic domain of matrix metalloproteinases (MMP-2, MMP-7 and MMP-9) by binding to the S1’ pocket of MMP-2 and MMP-9 and the catalytic Zn ion binding site of MMP-7, and that (ii) TD-11 can cause local disruption of the secondary structure of vascular endothelial growth factor A (VEGFA) dimer and exhibit stable interaction at the binding interface of VEGFA receptor R1 complex. Cell-culture-based in vitro experiments showed anti-metastatic phenotypes as seen in migration and invasion assays in cancer cells by both TD-10 and TD-11. Underlying biochemical evidence revealed downregulation of VEGF and MMPs at the protein level; MMP-9 was also downregulated at the transcriptional level. By molecular analyses, we demonstrate that TD-10 and TD-11 target stress chaperone mortalin at the transcription and translational level, yielding decreased expression of vimentin, fibronectin and hnRNP-K, and increase in extracellular matrix (ECM) proteins (collagen IV and E-cadherin) endorsing reversal of epithelial–mesenchymal transition (EMT) signaling.

Original languageEnglish
Article number5463
Pages (from-to)1-23
Number of pages23
JournalInternational Journal of Molecular Sciences
Volume21
Issue number15
DOIs
StatePublished - 2020 Aug 1

Keywords

  • ECM enhancer
  • EMT reversal
  • Inhibitor
  • MMP
  • Mortalin
  • Triethylene glycol derivatives
  • VEGF

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