Experimental and Computational Studies Reveal Novel Interaction of Lymphocytes Antigen 6K to TGF-β Receptor Complex.
Justyna Andrys-OlekBenson Chellakkan SelvanesanSheelu VargheseRicardo Hernandez ArriazaPurushottam Babu TiwariMaksymilian ChruszczTomasz BorowskiGeeta UpadhyayPublished in: International journal of molecular sciences (2023)
TGF-β signaling promotes migration, invasion, and distant colonization of cancer cells in advanced metastatic cancers. TGF-β signaling suppresses the anti-tumor immune response in a tumor microenvironment, allowing sustained tumor growth. TGF-β plays an important role in normal physiology; thus it is no surprise that the clinical development of effective and safe TGF-β inhibitors has been hampered due to their high toxicity. We discovered that increased expression of LY6K in cancer cells led to increased TGF-β signaling and that inhibition of LY6K could lead to reduced TGF-β signaling and reduced in vivo tumor growth. LY6K is a highly cancer-specific protein, and it is not expressed in normal organs except in the testes. Thus, LY6K is a valid target for developing therapeutic strategies to inhibit TGF-β signaling in cancer cells. We employed in vitro pull-down assays and molecular dynamics simulations to understand the structural determinants of the TGF-β receptor complex with LY6K. This combined approach allowed us to identify the critical residues and dynamics of the LY6K interaction with the TGF-β receptor complex. These data are critical in designing novel drugs for the inhibition of TGF-β in LY6K expressing cancer, induction of anti-tumor immune response, and inhibition of tumor growth and metastatic spread.
Keyphrases
- transforming growth factor
- immune response
- molecular dynamics simulations
- squamous cell carcinoma
- epithelial mesenchymal transition
- binding protein
- papillary thyroid
- lymph node
- oxidative stress
- poor prognosis
- inflammatory response
- molecular docking
- young adults
- electronic health record
- big data
- single cell
- amino acid
- lymph node metastasis