Retinoic acid receptor gamma impacts cellular adhesion, Alpha5Beta1 integrin expression and proliferation in K562 cells

The interplay between cellular adhesion and proliferation is complex; however, integrins, particularly the alpha 5 beta 1 subset, play a pivotal role in orchestrating critical cellular signals that culminate in cellular adhesion and growth. Retinoids modify the expression of a variety of adhesive/proliferative signaling proteins including alpha 5 beta 1 integrins; however, the role of specific retinoic acid receptors involved in these processes has not been elucidated. In this study, the effect of all-trans-retinoic acid receptor (RAR) agonists on K562 cellular adhesion, proliferation, and alpha 5 beta 1 integrin cell surface expression was investigated. RAR. agonist exposure increased K562 cellular adhesion to RGD containing extracellular matrix proteins fibronectin and FN-120 in a time-and concentration dependent manner, while RAR alpha or RAR beta agonist treatment had no effect on cellular adhesion. Due to the novel RAR gamma-dependent cellular adhesion response exhibited by K562 cells, we examined alpha 5 and beta 1 integrin subunit expression when K562 cells were exposed to retinoid agonists or vehicle for 24, 48, 72 or 96 hours. Our data demonstrates no differences in K562 cell surface expression of the a5 integrin subunit when cells were exposed to RAR alpha, RAR beta, or RAR gamma agonists for all time points tested. In contrast, RAR gamma agonist exposure resulted in an increase in cell surface beta 1 integrin subunit expression within 48 hours that was sustained at 72 and 96 hours. Finally, we demonstrate that while exposure to RAR alpha or RAR beta agonists have no effect on K562 cellular proliferation, the RAR gamma agonist significantly dampens K562 cellular proliferation levels in a time-and concentration-dependent manner. Our study is the first to report that treatment with a RAR gamma specific agonist augments cellular adhesion to alpha 5 beta 1 integrin substrates, increases cell surface levels of the beta 1 integrin subunit, and dampens cellular proliferation in a time and concentration dependent manner in a human erythroleukemia cell line.