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 HCA2-induced Akt activation remain to be elucidated. Using CHO-K1 cells stably expressing HCA2 and A431 cells, a human epidermoid cell line with high levels of endogenous expression of functional HCA2 receptors, we first demonstrated that niacin induced a robust Akt phosphorylation at both Thr308 and Ser473 in a time-dependent fashion, with a maximal activation at 5 min and a subsequent reduction to baseline by 30 min through HCA2, and that the activation was significantly blocked by pertussis toxin. The HCA2-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-HCA2 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 HCA2-mediated Akt activation. Further investigation indicated that PI3K and the Gβγ subunit were likely to play an essential role in HCA2-induced Akt activation. Moreover, Immunobloting analyses using an antibody that recognizes p70S6K1 phosphorylated at Thr389 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 HCA2 activation.
Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Huawang
H
Sun
College of Life Sciences, Zijingang Campus, Zhejiang University, Hangzhou, Zhejiang, China; Institute of Aging Research, Hangzhou Normal University, Hangzhou, Zhejiang, China.
Guo
G
Li
Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Wenjuan
W
Zhang
Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Qi
Q
Zhou
Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Yena
Y
Yu
College of Life Sciences, Zijingang Campus, Zhejiang University, Hangzhou, Zhejiang, China.
Ying
Y
Shi
Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
Stefan
S
Offermanns
Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Jianxin
J
Lu
College of Life Sciences, Zijingang Campus, Zhejiang University, Hangzhou, Zhejiang, China.
Naiming
N
Zhou
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009525:Niacin / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects*
C530636:HCAR2 protein, human; C473652:Hcar2 protein, mouse; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D009525:Niacin; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C