Antagonistic role of Klotho-derived peptides dynamics in the pancreatic cancer treatment through obstructing WNT-1 and Frizzled binding

Klotho is an anti-aging protein that is engaged in the suppression of canonical WNT signaling. In this study, we investigated the expression pattern of human WNTs and Klotho in the pancreatic cancer. In the cancerous cells, WNT-1 exhibited much higher expression as compared to other WNTs, while no WNT expression was detected in the normal tissue. In contrast, Klotho expression was significantly low in the cancerous tissue. Based on these observations, we intended to explore Klotho binding to WNT-1 and cystein-rich domains (CRDs) of Frizzled (FZD) homologs through molecular docking and dynamics simulation assays. Interestingly, similar region of WNT-1 was detected in binding with Klotho and CRDs of FZD-1/2. FZD-CRDs were grasped by the association of peripheral hydrophobic residues of WNT-1 U-shaped cavity. Subsequently, WNT-1-bound Klotho-peptides were isolated and reevaluated for their binding abilities against WNT-1 and FZD-CRDs., The conformational readjustements of these complexes were deeply analyzed by calculating the size of WNT-1 U-shaped cavity. In comparison to apo-WNT-1, cavity opening was markedly enhanced (8.2 angstrom to 15.64 angstrom, 32.89 angstrom and 35.11 angstrom) inWNT-1-a, WNT-1-c and WNT-1-e complexes, respectively. Thus Klotho-derived peptides may facilitate distinct conformational changes in the WNT-1-FZD associated region. As a result, aberrant loss of FZD binding may lead to augment WNT signaling. Overall, current study opens up new avenues in the pancreatic cancer therapeutics through antagonizing WNT-1 by Klotho.