obeticholic-acid and pregna-4-17-diene-3-16-dione

The nuclear receptor, farnesoid X receptor (FXR), has been recently considered as a tumor suppressor in HCC. IL-6/Janus kinase 2 (Jak-2)/signal transducer and activator of transcription 3 (STAT3) pathway has been implicated as a key player in many cancer types. This study aimed at investigating the potential effect of the FXR agonist, obeticholic acid (OCA), on HCC and the involvement of IL-6/STAT3 pathway. The potential regulation of STAT3 by its main feedback inhibitor target gene, the suppressor of cytokine signaling 3 (SOCS3), triggered by OCA was also explored. Cytotoxicity studies were performed on HepG2, Huh7, and SNU-449 cell lines using OCA alone and combined with the FXR antagonist guggulsterone (Gugg). OCA cytotoxic effect was significantly hampered in presence of Gugg. OCA also caused cell cycle arrest and inhibited invasion and migration of HCC cells. Decrease in STAT3 phosphorylation and SOCS3 upregulation were also observed. Moreover, Jak-2, IL-1β, and IL-6 levels were decreased. These results were correlated with an upregulation of FXR and small heterodimer partner (SHP) levels. Effects of OCA on IL-6/STAT3 main key players were reversed in presence of Gugg. Overall, these findings suggest a potential effect of OCA in HCC via interfering with IL-6/STAT3 signalling pathway in vitro.

Topics: Antineoplastic Agents, Phytogenic; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chenodeoxycholic Acid; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Hepatocytes; Humans; Interleukin-1beta; Interleukin-6; Janus Kinase 2; Pregnenediones; Receptors, Cytoplasmic and Nuclear; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein

Portal hypertension is a frequent pathological symptom occurring especially in hepatic fibrosis and cirrhosis. Current paradigms indicate that inhibition of hepatic stellate cell (HSC) activation and contraction is anticipated to be an attractive therapeutic strategy, because activated HSC dominantly facilitates an increase in intrahepatic vein pressure through secreting extracellular matrix and contracting. Our previous in vitro study indicated that dihydroartemisinin (DHA) inhibited contractility of cultured HSC by activating intracellular farnesoid X receptor (FXR). However, the effect of DHA on fibrosis-related portal hypertension still requires clarification. In this study, gain- and loss-of-function models of FXR in HSC were established to investigate the mechanisms underlying DHA protection against chronic CCl

Topics: Animals; Artemisinins; Carbon Tetrachloride; Cell Death; Chenodeoxycholic Acid; Gene Expression; Hepatic Stellate Cells; Hepatocytes; Humans; Hypertension, Portal; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred ICR; Mice, Transgenic; Portal Vein; Pregnenediones; Protective Agents; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear