title: Sorafenib induces autophagic cell death and apoptosis in hepatic stellate cell through the JNK and Akt signaling pathways.
abstract: Increasing hepatic stellate cell (HSC) death is an attractive approach for limiting liver fibrosis. We investigated the molecular mechanisms underlying the effects of sorafenib on HSCs. LX2 cells were incubated with sorafenib and a variety of inhibitors of apoptosis, autophagy, and necrosis. Electron microscopy was used to observe autophagosomes. Inhibitors and siRNA were used to examine the role of the Akt/mTOR/p70S6K and JNK pathways. Ultrastructural analysis revealed that rat HSCs treated with 5 μmol/l sorafenib accumulated residual digested material and empty or autophagic vacuoles. Incubating LX2 cells with lysosomal protease inhibitors increased the accumulation of LC3-II, indicating that sorafenib enhances autophagic flux in HSCs. Autophagy may precede apoptosis. Lower concentrations of sorafenib and a shorter treatment time resulted in the dominance of autophagic cell death over apoptosis. Further analysis showed that Beclin 1 is inactivated by the caspases induced by sorafenib during apoptosis. Inhibition of autophagy in LX2 cells using 3-methyladenine treatment or siRNA-mediated knockdown of Atg5 resulted in a marked increase in apoptosis. Finally, sorafenib induced programmed cell death by attenuation and activation of Akt/mTOR/p70S6K and JNK signaling. Sorafenib-induced cell death is mediated by both autophagy and apoptosis. Elucidation of the signaling pathways activated by sorafenib could potentially lead to novel antifibrosis therapies for chronic liver diseases.
authors.affiliation: aDepartment of Gastroenterology, The Second Hospital of Hebei Medical University, Heibei Key Laboratory of Gastroenteroloyg, Hebei Institute of Gastroenterology, Shijiazhuang, China bDepartment of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Huiyao
authors.initials: H
authors.lastname: Hao
authors.forename: Di
authors.initials: D
authors.lastname: Zhang
authors.forename: Junli
authors.initials: J
authors.lastname: Shi
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Yongze
authors.initials: Y
authors.lastname: Guo
authors.forename: Junji
authors.initials: J
authors.lastname: Ma
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Jiang
authors.forename: Huiqing
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases