Integrin alpha 2 beta 1 inhibition attenuates prostate cancer cell proliferation by cell cycle arrest, promoting apoptosis and reducing epithelial-mesenchymal transition

Abstract

Integrin alpha 2 beta 1 plays an important role in cellular migration and metastasis processes associated with prostate cancer. The aim of this study was to assess whether selective inhibition of integrin alpha 2 beta 1 is an effective strategy to target metastatic prostate cancer cells. In this regard, we examined the effects of the inhibitor BTT-3033, which selectively interferes with the connection between integrin a2b1 and its ligand, on migration, epithelial-mesenchymal transition (EMT), cell cycle arrest, apoptosis, and specific intracellular signaling pathways using LNcap-FGC and DU-145 prostate cancer cell lines. Western blot analysis and immunocytochemistry assays showed that inhibition of integrin a2b1 inhibits EMT, through the increased expression of E-cadherin and decreased expression of N-cadherin and vimentin. Scratch wound healing assays revealed a direct effect on integrin alpha 2 beta 1 in the migration capacity of cells. In addition, treatment with BTT-3033 induced a reduction in cell viability and proliferation, as assessed by MTT and BrdU assays. In addition, the results show that BTT-3033 inhibits cell proliferation by inducing G1 cell cycle arrest. Moreover, inhibition of integrin alpha 2 beta 1 induces apoptosis through the activation of ROS, Bax protein upregulation, caspase-3 activation, and depletion of Delta psi m. Molecular signaling studies showed that integrin alpha 2 beta 1 was a positive regulator of MKK7 phosphorylation. In conclusion, our results reveal a critical role for integrin a2b1 in the proliferation of prostate cancer cells, as demonstrated by EMT inhibition, cell cycle arrest, and apoptosis induction in response to treatment with its specific inhibitor BT-3033.