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.

Advances in Pharmacological Activities of Terpenoids

“…[26][27][28][29] The current investigation demonstrated that ursolic acid could protect hepatoma cells and reduce HBx-mediated autophagy through modulation of Ras homolog gene family member A (RhoA). 26 In the present study, it was found that ursolic acid at the low micromolar range may promote its anticancer action by targeting glycolysis in phenotypically distinct breast cancer cells. 27 Ursolic acid can also inhibit proliferation and induce apoptosis of human osteosarcoma 143B cells by inactivating Wnt/β-catenin signaling.…”

Reactive Oxygen Species-Mediated Autophagy by Ursolic Acid Inhibits Growth and Metastasis of Esophageal Cancer Cells

“…Several studies have shown that UA possesses anti-proliferative, pro-apoptotic, anti-inflammatory, anti-metastatic, and antiangiogenic properties against cancer cells [17][18][19][20][21][22][23]. UA inhibits cell proliferation, arrests cell cycle progression, and reduces tumorigenesis through multiple signaling pathways [24][25][26][27][28][29][30][31][32][33]. Pentacyclic triterpenoid compounds have been found to display their anticancer properties by altering the levels of reactive oxygen species (ROS), derivatives of oxygen metabolism that are generated under conditions of cellular oxidative stress.…”

Isolasi Sinensetin dari Kumis Kucing (Orthosiphon aristatus Blume miq.) Varietas Putih

“…Pada masa pandemi Covid-19 penemuan senyawa atau tanaman obat tradisional yang berpotensi sebagai antivirus dan imunomodulator terus dilakukan dan berdasarkan hasil penelitian senyawa yang terkandung dalam tanaman kumis kucing berpotensi sebagai inhibitor Covid-19 (Sarkar & Das ;Rowaiye et al, 2020;Sekiou et al, 2020;Adem et al, 2020;Dahab et al, 2020;Narkhede et al, 2020;Sharma & Kaur, 2020;Faramayuda et al, 2021), antiherpetik (Ikeda et al, 2011;Medini et al, 2016;Astani et al, 2011;Astani & Schnitzler, 2014;Bourne et al, 1999;Benencia & Courreges, 2000;Sharifi-Rad et al, 2018), anti-human immunodeficiency virus (HIV) (Lin et al, 1999;McDougall et al, 1998;Zhang et al, 2014;Mengoni et al, 2002;Kashiwada et al, 1998;Xu et al, 1996), anti hepatitis (Haid et al, 2012;Duan et al, 2016;Kong et al, 2013;Chang et al, 2016) dan imunomodulator (Harun et al, 2015;Woottisin et al, 2011;Friedman, 2015;Kim et al, 2008;Takano et al, 2004;Sanbongi et al, 2004;Youn et al, 2003).…”