title: Induction of autophagy in hepatocellular carcinoma cells by SB203580 requires activation of AMPK and DAPK but not p38 MAPK.
abstract: SB203580 is a well-known inhibitor of p38 mitogen-activated protein kinase (MAPK). However, it can suppress cell proliferation in a p38 MAPK independent manner. The inhibitory mechanism remains unknown. Here, we showed that SB203580 induced autophagy in human hepatocellular carcinoma (HCC) cells. SB203580 increased GFP-LC3-positive cells with GFP-LC3 dots, induced accumulation of autophagosomes, and elevated the levels of microtubule-associated protein light chain 3 and Beclin 1. It stimulated the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and p53, but inhibited the phosphorylation of death-associated protein kinase (DAPK). Inhibition of AMPK, p53, or DAPK attenuated SB203580-induced autophagy. AMPK activation appeared to predate the DAPK signal. The activation of both AMPK and DAPK prompted the phosphorylation of p53 and enhanced Beclin 1 expression. Neither the downregulation of p38 MAPK by its siRNA or chemical inhibitor nor the upregulation of p38 MAPK by p38 MAPK DNA transfection affected B203580-induced autophagy. Collectively, the findings demonstrate a novel function of SB203580 to induce autophagy via activating AMPK and DAPK but independent of p38 MAPK. The induction of autophagy can thus account for the antiproliferative effect of SB203580 in HCC cells.
authors.affiliation: Department of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhang
authors.forename: George G
authors.initials: GG
authors.lastname: Chen
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Zhang
authors.forename: Sukying
authors.initials: S
authors.lastname: Chun
authors.forename: Billy Cheuk Sing
authors.initials: BC
authors.lastname: Leung
authors.forename: Paul B S
authors.initials: PB
authors.lastname: Lai
mesh_terms: D055372:AMP-Activated Protein Kinases; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D045744:Cell Line, Tumor; D064550:Death-Associated Protein Kinases; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D011725:Pyridines / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; C093642:SB 203580