TY - JOUR
T1 - Experimental and Computational Studies Reveal Novel Interaction of Lymphocytes Antigen 6K to TGF-β Receptor Complex
AU - Andrys-Olek, Justyna
AU - Selvanesan, Benson Chellakkan
AU - Varghese, Sheelu
AU - Arriaza, Ricardo Hernandez
AU - Tiwari, Purushottam Babu
AU - Chruszcz, Maksymilian
AU - Borowski, Tomasz
AU - Upadhyay, Geeta
N1 - Publisher Copyright:
© 2023 by the authors.
PY - 2023/8
Y1 - 2023/8
N2 - 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.
AB - 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.
KW - LY6K
KW - receptor complex
KW - TGF-β signaling
KW - TGF-β1
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U2 - 10.3390/ijms241612779
DO - 10.3390/ijms241612779
M3 - Article
C2 - 37628960
AN - SCOPUS:85168755185
SN - 1661-6596
VL - 24
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 16
M1 - 12779
ER -