Research Article: Integrin α5β1 simultaneously controls EGFR-dependent proliferation and Akt-dependent pro-survival signaling in epidermoid carcinoma cells

Date Published: May 22, 2012

Publisher: Impact Journals LLC

Author(s): Galina E Morozevich, Nadezda I Kozlova, Natalia A Ushakova, Marina E Preobrazhenskaya, Albert E Berman.

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Abstract

To delineate distinctive role of the components of α5β1 integrin-EGFR axis in control of epidermoid carcinoma cell proliferation, we performed individual inhibition of α5β1 and EGFR via genetic and phamacological methods, respectively. We demonstrated that pharmacological inhibition of epidermal growth factor receptor (EGFR) significantly affected proliferation of A431 human cells by inducing the G0/G1 cell cycle arrest, whereas shRNA-mediated depletion of α5 subunit of α5β1 integrin led to a similar type of cell cycle arrest followed by significant apoptosis. Both treatments resulted in suppression of activated (phosphorylated) forms of focal adhesion kinase (FAK) and Erk. However, unlike EGFR inhibition, depletion of α5 led to substantial suppression of AKT activity. Accordingly, pharmacological inhibition of EGFR and AKT recapitulated detrimental effects caused by shRNA-mediated depletion of α5. Moreover, depletion of α5 led to a severe drop in the amounts of active EGFR. Thus, for the first time, we demonstrated that α5β1 integrin simultaneously maintains pro-survival signaling via continuous activation of AKT and up-regulates proliferation via activation of EGFR.

Partial Text

Cell proliferation is controlled by cytokines including growth factors and the components of extracellular matrix. Both types of proteins initiate signal transduction through growth factor specific receptors and matrix-specific receptors integrins, and their disbalance may lead to the uncontrolled proliferation and carcinogenesis [1-4]. Different integrins can interact with the same matrix proteins thus generating physiologically similar signals [5] making evaluation of the functional impact of individual integrins a cumbersome task.

The role of α5β1 integrin in regulation of proliferation of normal and malignant cells is controversial. The expression of α5β1 was higher in proliferating retinal cells than in their quiescent counterparts [9]. Activation of α5β1 by its ligand fibronectin enhanced proliferation of cultured endothelium of lymphoid vessels [21]. Furthermore, growth rates of preadipocytes increased after the exogenous expression of α5β1 [22]. Likewise, the specific inhibitor of α5β1, JSM6427, caused retardation of proliferation of glioma [23] and endothelial [24] cells. On the other hand, inhibitory effects of α5β1 on cell proliferation have also been reported.Overexpression of α5β1 in Caco-2 and HT-29 colon cancer cells with low endogenous levels of this integrin abrogated their tumorigenicity [6]. Accordingly, it has been suggested that the inhibitory effects of tocopherol (vitamin E) on glioma cell proliferation were associated with higher expression of α5β1 [7]. It is conceivable that one of the reasons for these discrepancies is the cell type specific mechanisms of α5β1 signaling. Therefore, a detailed characterization of α5β1-mediated pathways in individual cell types emerges as an important question.

 

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