Integrin α6β4-Src-AKT signaling induces cellular senescence by counteracting apoptosis in irradiated tumor cells and tissues

Cellular senescence refers to an irreversible growth arrest that is triggered by various intrinsic and extrinsic stresses. Many recent studies have demonstrated that cellular senescence plays a crucial role in the regression of tumors exposed to ionizing radiation (IR), but the underlying mechanism remains unknown. Here we show that the activation of integrin beta 4 is essential for IR-induced cellular senescence. IR treatment results in the phosphorylation of integrin beta 4 at tyrosine residue 1510, leading to activation of the integrin alpha 6 beta 4-Src-AKT signaling pathway. We further reveal that the IR-induced phosphorylation of integrin beta 4 is regulated by the cholesterol content and membrane fluidity. We also find that IR-induced p53-caspase signaling is independent of integrin alpha 6 beta 4-Src-AKT signaling. Finally, we show that siRNA-or inhibitor-mediated blockade of integrin alpha 6 beta 4-Src-AKT signaling switches the post-irradiation fate from senescence to apoptosis, under p53 activated condition, in both cancer cells and tumor tissues of xenograft mice. On the basis of our finding that, integrin alpha 6 beta 4 is specifically activated and acts primarily to induce premature senescence in irradiated cancer cells, we propose that this integrin may be a valuable target and biomarker for radiotherapy.