Niacin Activates the PI3K/Akt Cascade via PKC- and EGFR-Transactivation-Dependent Pathways through Hydroxyl-Carboxylic Acid Receptor 2

Niacin has been demonstrated to activate a PI3K/Akt signaling cascade to prevent brain damage after stroke and UV-induced skin damage; however, the underlying molecular mechanisms for HCA(2)-induced Akt activation remain to be elucidated. Using CHO-K1 cells stably expressing HCA(2) and A431 cells, a human epidermoid cell line with high levels of endogenous expression of functional HCA(2) receptors, we first demonstrated that niacin induced a robust Akt phosphorylation at both Thr(308) and Ser(473) in a time-dependent fashion, with a maximal activation at 5 min and a subsequent reduction to baseline by 30 min through HCA(2), and that the activation was significantly blocked by pertussis toxin. The HCA(2)-mediated activation of Akt was also significantly inhibited by the PKC inhibitors GF109203x and Go6983 in both cell lines, by the PDGFR-selective inhibitor tyrphostin A9 in CHO-HCA(2) cells and by the MMP inhibitor GM6001 and EGFR-specific inhibitor AG1478 in A431 cells. These results suggest that the PKC pathway and PDGFR/EGFR transactivation pathway play important roles in HCA(2)-mediated Akt activation. Further investigation indicated that PI3K and the G(βγ) subunit were likely to play an essential role in HCA(2)-induced Akt activation. Moreover, Immunobloting analyses using an antibody that recognizes p70S6K1 phosphorylated at Thr(389) showed that niacin evoked p70S6K1 activation via the PI3K/Akt pathway. The results of our study provide new insight into the signaling pathways involved in HCA(2) activation.