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

Abstract

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 β4 is essential for IR-induced cellular senescence. IR treatment results in the phosphorylation of integrin β4 at tyrosine residue 1510, leading to activation of the integrin α6β4-Src-AKT signaling pathway. We further reveal that the IR-induced phosphorylation of integrin β4 is regulated by the cholesterol content and membrane fluidity. We also find that IR-induced p53-caspase signaling is independent of integrin α6β4-Src-AKT signaling. Finally, we show that siRNA- or inhibitor-mediated blockade of integrin α6β4-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 α6β4 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.

ITGB4 deficiency induces senescence of airway epithelial cells through p53 activation

“…By RNA interference, ITGB4 deficiency inhibits the cell division cycle and proliferation in vitro . ITGB4 has also been shown to be associated with aging in many different cells . Here, our results also verified that ITGB4 deficiency induced senescence‐like changes of airway epithelial cells in vivo and in vitro .…”

“…Besides, it has also been demonstrated that after house dust mite stress, ITGB4 defects in airway epithelial cells conferred increased airway hyper‐responsiveness and aggravated airway inflammation compared with wild‐type mice . Notably, ITGB4 has also been shown to be associated with senescence in many different cells . Senescence is controlled by two major senescence pathways, p53–p21 WAF1/CIP1 and Rb–p16 INK4a13 .…”

Exosome-derived ENO1 regulates integrin α6β4 expression and promotes hepatocellular carcinoma growth and metastasis

“…Integrins are the key players in tumor cell spread and are expressed at different levels at different stages of tumor development. Dysregulation of integrins can alter their functions, causing tumor cells to detach from the basement membrane and lose polarity, and these increased free integrins participate in bidirectional signal transduction in tumors [46][47][48] . Two key proteins, FAK and Src, important regulatory proteins affected by integrin α6β4, are closely related to tumor growth and metastasis and are activated through a series of phosphorylation events.…”

Cellular senescence: a promising strategy for cancer therapy

“…The senescent cells become flat and enlarged due to rearrangement of the cytoskeleton. Their plasma membrane composition is changed by the up-regulation of caveolin-1, a main component of caveolae (34, 35). Senescent cells also have an increased cholesterol content in membrane and large and dysfunctional mitochondria (34, 35).…”

“…Their plasma membrane composition is changed by the up-regulation of caveolin-1, a main component of caveolae (34, 35). Senescent cells also have an increased cholesterol content in membrane and large and dysfunctional mitochondria (34, 35). Lysosomal content and lysosomal enzyme senescence-associated β-galactosidase (SA-β-gal) is highly upregulated during senescence (36).…”