Integrin-mediated signaling contributes to gadolinium-containing-particle-promoted cell survival and G₁ to S phase cell cycle transition by enhancing focal adhesion formation.

We previously reported that Gd-containing particles formed under physiological conditions act as active entities to enhance cell survival and promote S phase entry via activation of both mitogen-activated protein kinase/extracellular-signal-regulated protein kinase (ERK) and phosphatidylinositol 3-kinase/Akt signaling pathways. However, how they transduce the extracellular signal inside the cell remains unclear. The present study demonstrates that Gd-containing particles can alleviate serum-deprivation-induced cell death and promote G₁ to S phase cell cycle progression by enhancing cell adhesion to the extracellular matrix. As an indicator of adhesion, the vinculin distribution was detected by confocal laser scanning microscopy. The control cells exhibited fewer and less typical focal adhesions. After treatment with Gd-containing particles, a large number of vinculin-containing focal adhesions were maintained. In the presence of integrin antagonists, the percentage of S phase entry induced by Gd-containing particles was decreased and the enhancement of cell viability was also attenuated, along with a decrease in both cyclin D expression and ERK phosphorylation. In summary, the present results suggest that the integrin-mediated signaling pathway plays an important role in cell survival and G₁ to S phase transition promoted by Gd-containing particles by enhancing focal adhesion formation. The results presented here provide novel evidence to advance knowledge leading to further understanding of the mechanisms of both cell proliferation and cell survival promoted by Gd and may be helpful for developing effective measures to prevent or treat nephrogenic systemic fibrosis.