UV and H2O2 induce AMPK activation in cultured skin keratinocytes

Abstract

AMP‐activated protein kinase or AMPK is an evolutionarily conserved sensor of cellular energy status, activated by a variety of cellular stresses that deplete ATP as well as other stresses. However, the possible involvement of AMPK in UV‐ and H2O2 ‐induced skin aging is not fully studied. We show for the first time that UV and H2O2 induce AMPK activation in cultured human skin keratinocytes (HaCaT cells). UV and H2O2 also induce LKB1, the possible upstream signal of AMPK, in an EGFR dependent manner. Using Compound C, a specific inhibitor of AMPK and AMPK specific siRNA knockdown as well as AMPK activator AICAR, we found that AMPK serves as a positive regulator for p38 and p53 (ser 15) activation induced by UV radiation or H2O2 treatment. We also observed that AMPK activation pathway serves a negative feedback signal pathway against UV‐induced mTOR activation in a TSC2 dependent manner. Inhibiting mTOR and activating p53 and p38 may mediate AMPK's pro‐apoptotic effect in UV or H2O2 treated cells. Furthermore, activation AMPK also phosphorylates acetyl‐CoA carboxylase or ACC, the pivotal enzyme of fatty acid synthesis, and PFK2, the key protein of glycolysis in UV‐radiated cells which may explain reduced adipogenesis in UV or H2O2 treated 3T3‐L1 adipocyte and skin keratinocytes. Collectively, our results demonstrate that UV and H2O2 induce EGFR/LKB1/AMPK signal pathway activation in cultured skin keratinocytes, which plays important role on UV or H2O2‐induced signal transduction and skin aging.