Retinoic acid-induced growth arrest of MCF-7 cells involves the selective regulation of the IRS-1/PI 3-kinase/AKT pathway

The phosphoinositide 3-kinase/Akt pathway is essential for the retinoic acid-induced differentiation of F9 cells

“…Later RA-induced decrease in Akt activity is PI3K independent The present study shows that RA also induces a late inhibition of the PI3K/Akt pathway, in F9 cells as well as in other cell types, in agreement with other reports (del Rincon et al, 2003;del Rincon et al, 2004;Farias et al, 2005). Different hypothesis have been proposed concerning the mechanism through which RA inhibits the PI3K/Akt pathway but all the studies converged towards the conclusion that RA inhibits PI3K by preventing the association of the regulatory p85a with the p110 catalytic subunit and thus the formation of the active heterodimers.…”

Retinoic acid mediates degradation of IRS-1 by the ubiquitin–proteasome pathway, via a PKC-dependant mechanism

“…Regulation of IRS-1 protein levels in MCF-7 cells and other retinoid-responsive breast cancer cell lines Consistent with our previous findings, exposure of MCF-7 cells to 1 mM RA for 72 h in serum-free media (SFM) results in a dose-dependant decrease in IRS-1 protein levels ( Figure 1a) (del Rinco´n et al, 2003). Previous studies have shown that antiestrogens and glucocorticoids alter IRS-1 levels (Turnbow et al, 1994;Salerno et al, 1999;Chan et al, 2001;Buren et al, 2002); thus, we investigated whether other nuclear receptor-selective ligands would induce a similar decrease in IRS-1 levels.…”

“…We previously showed that RA-mediated growth arrest of MCF-7 cells involves a decrease in IRS-1 protein levels (del Rinco´n et al, 2003), and others have associated G1 arrest of bronchial epithelial cells with an RA-mediated decrease of cyclin D1 protein levels (Langenfeld et al, 1997;Boyle et al, 1999) and RA-mediated differentiation of F9 embryonal carcinoma cells with a decrease in the protein levels of the transcriptional coactivator, p300 (Iwao et al, 1999;Brouillard and Cremisi, 2003). Although the past two decades have focused on examining transcriptional mechanisms linked to the pleiotropic effects of RA, the importance of post-translational modification of various proteins has been recently highlighted.…”

Insulin Receptor Substrate-1 Is an Important Mediator of Ovarian Cancer Cell Growth Suppression by All-trans Retinoic Acid

“…Several studies have shown that retinoids inhibit breast cancer cell growth through interference in the IGF-IR signaling pathway. Inhibition of IGF-Istimulated growth, increased production of IGF-binding protein 3 and, recently, down-regulation of Akt pathway due to degradation of IRS-1 (20,21) are some of the mechanisms by which retinoids inhibit growth of breast cancer cells.…”