ROS-activated p38 MAPK/ERK-Akt cascade plays a central role in palmitic acid-stimulated hepatocyte proliferation |
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Authors: | Wang Xin Liu Jiang Z Hu Jun X Wu Hao Li Yu L Chen Hong L Bai Hua Hai Chun X |
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Affiliation: | Department of Toxicology, Faculty of Preventive Medicine, the Fourth Military Medical University, Xi''an, 710032, China |
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Abstract: | In the past years, free fatty acids (FFAs) and obesity have been reported to play an important role in cancer development. Palmitic acid (PA) is the most prevalent saturated FFA in circulation. However, the mechanism underlying the effect of PA on cell proliferation is still to be elucidated. In this report, we, for the first time, investigate the signaling pathway in human normal hepatocytes (QZG) responsible for PA-induced proliferation. The results demonstrate that PA promotes cell cycle progression, accelerates cell proliferation, and induces a transient and sequential activation of a series of kinases. The employment of several inhibitors and antioxidants indicates that a ROS-induced stress-sensitive p38 MAPK/ERK-Akt cascade plays a critical role in the regulation of PA on cell cycle and cell proliferation. Moreover, PA dose and time dependently activates Nrf2 and this activation relies on ROS-induced stimulation of p38 MAPK/ERK-Akt signaling, demonstrating that Nrf2 activation may be associated with the regulation of PA on cell cycle transition and proliferation. In conclusion, our study elucidates the importance of PA metabolism on cell proliferation, and suggests that PA stimulates hepatocyte proliferation through activating the ROS-p38 MAPK/ERK-Akt cascade which is intersected with the activation of Nrf2 and that the effect of ROS on signal transduction is in a dose- and time-dependent manner. All the above noted provide a new clue for the central role of ROS in cell proliferation and tumorigenesis. |
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Keywords: | Akt, protein kinase B CAT, catalase CDKs, cyclin-dependent kinases ER, endoplasmic reticulum ERK, extracellular signal-regulated kinase FASN, fatty acid synthase FFAs, free fatty acids H2DCFDA, 2&prime ,7&prime -dichlorofluorescin diacetate JNK, c-Jun NH2-terminal kinase MAPKs, mitogen-activated protein kinases NAC, N-acetylcysteine Nrf2, nuclear factor erythroid 2 p45-related factor 2 OXPHOS, oxidative phosphorylation PA, palmitic acid PCNA, proliferating cell nuclear antigen Rb, retinoblastoma ROS, reactive oxygen species 3NP, 3 nitropropionic acid |
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