Implication of integrin α2β1 in senescence of SK-Mel-147 human melanoma cells

This investigation addressed the impact of integrin-initiated signaling pathways on senescence of tumor cells. In a model of human SK-Mel-147 melanoma cells, the silencing of integrin alpha 2 beta 1 strongly reduced cell proliferation and enhanced the percentage of SA-beta-Gal-positive cells, a phenotypic feature of cellular senescence. These changes were accompanied by a significant increase in the activity of Akt and mTOR protein kinases and also in the expression of p53 and p21 oncosuppressors. Pharmacological inhibition of Akt and mTORC1 and genetic inhibition of p53 and p21 reduced the senescence of alpha 2 beta 1-depleted SK-Mel-147 cells to the level of control cells. Based on our earlier data on the non-canonical functions of Akt isomers in the invasion and anoikis of SK-Mel-147 cells, we investigated the role of Akt isomers in senescence induced by alpha 2 beta 1 suppression. The inhibition of Akt1 strongly reduced the percentage of SA-beta-Gal-positive cells in the alpha 2 beta 1-depleted cell population, while the inhibition of Akt2 did not have a noticeable effect. Our data demonstrated for the first time that alpha 2 beta 1 is involved in the protection of tumor cells against senescence and that senescence, which is induced by the downregulation of alpha 2 beta, is based on a signaling mechanism in which Akt1 performs a non-canonical function.