TY - JOUR
T1 - Melatonin represses oxidative stress-induced activation of the MAP kinase and mTOR signaling pathways in H4IIE hepatoma cells through inhibition of Ras
AU - Kimball, Scot R.
AU - Abbas, Ahmed
AU - Jefferson, Leonard S.
PY - 2008/5
Y1 - 2008/5
N2 - Reactive oxygen species (ROS) have been implicated in the pathogenesis of a variety of diseases, and antioxidant treatment is currently being investigated as a potential therapy to attenuate the detrimental effects of ROS-mediated oxidative stress. Melatonin is a potent naturally produced antioxidant, which acts through various mechanisms to ameliorate the toxic effects of ROS. However, little is known about the mechanisms of signaling pathways through which melatonin acts to reverse the effects of ROS. In the present study, the effect of melatonin treatment on the hydrogen peroxide (H2O 2)-induced activation of the mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways was assessed in H4IIE hepatoma cells. It was found that melatonin strongly attenuated H 2O2-induced activation of the ERK1/2 and p38 MAP kinases, as well as several of their downstream targets. Melatonin also attenuated the H2O2-induced phosphorylation of Akt and the Akt substrate mTOR, as well as a downstream target of mTOR action, 4E-BP1. Upregulation of ERK1/2, p38, and Akt signaling by H2O2 was accompanied by activation of Ras, an effect that was blocked by melatonin. Overall, the results suggest that melatonin acts to prevent many of the H2O 2-induced alterations in the MAPK and mTOR signaling pathways through inhibition of Ras, at least in H4IIE hepatoma cells.
AB - Reactive oxygen species (ROS) have been implicated in the pathogenesis of a variety of diseases, and antioxidant treatment is currently being investigated as a potential therapy to attenuate the detrimental effects of ROS-mediated oxidative stress. Melatonin is a potent naturally produced antioxidant, which acts through various mechanisms to ameliorate the toxic effects of ROS. However, little is known about the mechanisms of signaling pathways through which melatonin acts to reverse the effects of ROS. In the present study, the effect of melatonin treatment on the hydrogen peroxide (H2O 2)-induced activation of the mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways was assessed in H4IIE hepatoma cells. It was found that melatonin strongly attenuated H 2O2-induced activation of the ERK1/2 and p38 MAP kinases, as well as several of their downstream targets. Melatonin also attenuated the H2O2-induced phosphorylation of Akt and the Akt substrate mTOR, as well as a downstream target of mTOR action, 4E-BP1. Upregulation of ERK1/2, p38, and Akt signaling by H2O2 was accompanied by activation of Ras, an effect that was blocked by melatonin. Overall, the results suggest that melatonin acts to prevent many of the H2O 2-induced alterations in the MAPK and mTOR signaling pathways through inhibition of Ras, at least in H4IIE hepatoma cells.
UR - http://www.scopus.com/inward/record.url?scp=42249099251&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=42249099251&partnerID=8YFLogxK
U2 - 10.1111/j.1600-079X.2007.00539.x
DO - 10.1111/j.1600-079X.2007.00539.x
M3 - Article
C2 - 18410586
AN - SCOPUS:42249099251
SN - 0742-3098
VL - 44
SP - 379
EP - 386
JO - Journal of Pineal Research
JF - Journal of Pineal Research
IS - 4
ER -