title: Ursolic Acid Suppresses Hepatitis B Virus X Protein-mediated Autophagy and Chemotherapeutic Drug Resistance.
abstract: Hepatitis B virus X (HBx) protein is a multifunctional oncoprotein that affects diverse cell activities via regulation of various host cell signaling pathways. The current investigation demonstrated that ursolic acid (UA), a pentacyclic triterpenoid, protected hepatoma cells and reduced HBx-mediated autophagy through modulation of Ras homolog gene family member A (RhoA). Low-level ectopic HBx expression in Huh7 cells induced more significant autophagosome formation than high-level HBx expression. HBx activated beclin-1 promoter and enhanced the beclin-1 protein expression under low HBx expression. Transcription factor AP-1 played an essential function in HBx-mediated beclin-1 promoter activation. Inhibition of RhoA and its downstream effector Rho-associated coiled-coil-containing protein kinase 1 (ROCK1) alleviated HBx-mediated autophagy significantly. Transiently-expressed HBx elicited an increased RhoA-GTP level, as well as phospho-ROCK1 transient accumulation. Utilization of transactivation-deficient HBx demonstrated that the transactivation activity of HBx is required for autophagy induction. Furthermore, UA suppressed HBx-mediated RhoA activation, beclin-1 promoter activation and subsequent autophagy induction, while, most importantly, reversed HBx-induced anti-cancer drug resistance.
authors: Department of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung, Taiwan, R.O.C.
authors: Ching-Dong
authors: CD
authors: Chang
authors: Research and Development Department, Golden Dapu Biotech Corp., Chiayi, Taiwan, R.O.C.
authors: Ping-Yuan
authors: PY
authors: Lin
authors: Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung, Taiwan, R.O.C.
authors: Jue-Liang
authors: JL
authors: Hsu
authors: Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung, Taiwan, R.O.C. wlshih@mail.npust.edu.tw.
authors: Wen-Ling
authors: WL
authors: Shih
mesh_terms: D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D000071186:Beclin-1 / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D054334:Viral Regulatory and Accessory Proteins; D054460:rho-Associated Kinases / Q000378:metabolism*; D000097245:Ursolic Acid
chemical_list: D000071186:Beclin-1; D049452:Green Fluorescent Proteins; D008156:Luciferases; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014315:Triterpenes; D054334:Viral Regulatory and Accessory Proteins; D054460:rho-Associated Kinases; D000097245:Ursolic Acid; C491997:BECN1 protein, human; C057628:hepatitis B virus X protein; C515851:ROCK1 protein, human
keywords: HBx; ROCK1; RhoA; autophagy; ursolic acid