Tissue transglutaminase activates integrin-linked kinase and β-catenin in ovarian cancer

Ovarian cancer (OC) is the most lethal gynecological cancer. OC cells have high proliferative capacity, are invasive, resist apoptosis, and tumors often display rearrangement of extra -cellular matrix (ECM) components, contributing to accelerated tumor progression. The multifunctional protein tissue trans-glutaminase (TG2) is known to be secreted in the tumor microenvironment, where it interacts with fibronectin (FN) and the cell surface receptor integrin beta 1. However, the mechanistic role of TG2 in cancer cell proliferation is unknown. Here, we demonstrate that TG2 directly interacts with and facilitates the phosphorylation and activation of the integrin effector protein integrin-linked kinase (ILK) at Ser246. We show that TG2 and p-Ser246-ILK form a complex that is detectable in patient -derived OC primary cells grown on FN-coated slides. In addi-tion, we show that coexpression of TGM2 and ILK correlates with poor clinical outcome. Mechanistically, we demonstrate that TG2-mediated ILK activation causes phosphorylation of glycogen synthase kinase-3 alpha/beta, allowing beta-catenin nuclear translocation and transcriptional activity. Furthermore, inhi-bition of TG2 and ILK using small molecules, neutralizing antibodies, or shRNA-mediated knockdown blocks cell adhe-sion to the FN matrix, as well as the Wnt receptor response to the Wnt-3A ligand, and ultimately, cell adhesion, growth, and migration. In conclusion, we demonstrate that TG2 directly interacts with and activates ILK in OC cells and tumors and define a new mechanism that links ECM cues with beta-catenin signaling in OC. These results suggest a central role of TG2- FN-integrin clusters in ECM rearrangement and indicate that downstream effector ILK may represent a potential new ther-apeutic target in OC.

Automated summary

The study demonstrates that TG2 interacts with and activates ILK in ovarian cancer cells and tumors, leading to cell adhesion, proliferation, and migration. Co-expression of TG2 and ILK correlates with poor clinical outcomes. These findings reveal a new mechanism that links extracellular matrix cues with beta-catenin signaling in OC.