Bioinformatics and Molecular Insights to Anti-Metastasis Activity of Triethylene Glycol Derivatives

• Published in: International journal of molecular sciences 2020-07, Vol.21 (15), p.5463
• Main Authors: Malik, Vidhi, Garg, Sukant, Afzal, Sajal, Dhanjal, Jaspreet Kaur, Yun, Chae-Ok, Kaul, Sunil C, Sundar, Durai, Wadhwa, Renu
• Format: Article
• Language: English
• Subjects: Angiogenesis; Antiangiogenics; Apoptosis; Bioinformatics; Biomarkers; Cadherins - genetics; Cancer; Cell adhesion & migration; Cell culture; Cell growth; Cell Line, Tumor; Cell Movement - drug effects; Collagen (type IV); Computational Biology; Drug dosages; E-cadherin; ECM enhancer; Epithelial-Mesenchymal Transition; Extracellular matrix; Fibronectin; Gelatinase A; Gelatinase B; Gene Expression Regulation, Neoplastic - drug effects; Glycol dimethacrylates; Growth factors; Heparan sulfate; Humans; Hypoxia; inhibitor; Kinases; Matrilysin; Matrix metalloproteinase; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 9 - genetics; Matrix metalloproteinases; Mesenchyme; Metastases; Metastasis; MMP; Molecular dynamics; Molecular structure; mortalin; Neoplasm Metastasis - drug therapy; Neoplasm Metastasis - pathology; Neoplasms - drug therapy; Neoplasms - pathology; Phenotypes; Polyethylene Glycols - chemistry; Polyethylene Glycols - therapeutic use; Protein structure; Proteins; Secondary structure; Signal Transduction - genetics; Transcription; triethylene glycol derivatives; Triethylene glycol dimethacrylate; Vascular endothelial growth factor; VEGF; Vimentin; Wound healing
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21155463

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.