title: Curcumol induces HSC-T6 cell death through suppression of Bcl-2: involvement of PI3K and NF-κB pathways.
abstract: The major feature in the molecular pathogenesis of hepatic fibrosis requires maintenance of the activated hepatic stellate cells (HSCs) phenotype by both proliferation and inhibition of apoptosis. Thus, the induction of activated HSCs apoptosis has been proposed as an antifibrotic treatment strategy. Curcumol has pro-apoptotic activity in a number of cancer cell types. The aim of this study is to test the hypothesis that the interruption of the phosphatidylinositol 3 kinase (PI3K)/nuclear factor-κB (NF-κB) signaling pathway by curcumol might induce apoptosis of activated HSCs. Our results indicated that curcumol-induced growth inhibition correlated with apoptosis induction as evidenced by Annexin V staining, and cleavage of caspase-3 and poly (ADP-ribose) polymerase (PARP) in HSC-T6. Importantly, we show that the apoptotic effect of curcumol was specific to the activated HSCs (HSC-T6). Suppression of the NF-κB translocation via inhibition of IκB-α phosphorylation by the curcumol led to the inhibition of expression of NF-κB-regulated gene, e.g. Bcl-xL and Bcl-2, in a PI3K-dependent manner, which is upstream of NF-κB activation. Also, curcumol-mediated apoptosis of HSC-T6 were reversed by LY294002 and Bay 11-7082. Taken together, our findings perfectly support the hypothesis and demonstrate that the inhibition of PI3K/NF-κB pathway by curcumol lead to HSC-T6 apoptosis. Thus, our study indicates that curcumol is a potential candidate for further preclinical study aimed at the treatment of liver fibrosis.
authors.affiliation: The Institute of Medicine, Qiqihar Medical University, 333 BuKui Street, JianHua District, Qiqihar 161006, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Rheumatoid Immunology Clinic, The First Affiliated Hospital to Changchun, University of Chinese Medicine, Changchun 130117, China.
authors.forename: Yinghang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Nursing, Qiqihar Medical University, Qiqihar 161006, China.
authors.forename: Meiqian
authors.initials: M
authors.lastname: Li
authors.affiliation: The Institute of Medicine, Qiqihar Medical University, 333 BuKui Street, JianHua District, Qiqihar 161006, China.
authors.forename: Tianjiao
authors.initials: T
authors.lastname: Xu
authors.affiliation: The Institute of Medicine, Qiqihar Medical University, 333 BuKui Street, JianHua District, Qiqihar 161006, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wang
authors.affiliation: The Institute of Medicine, Qiqihar Medical University, 333 BuKui Street, JianHua District, Qiqihar 161006, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Hong
authors.affiliation: The Institute of Medicine, Qiqihar Medical University, 333 BuKui Street, JianHua District, Qiqihar 161006, China. Electronic address: nyc1968@126.com.
authors.forename: Yingcai
authors.initials: Y
authors.lastname: Niu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D051381:Rats; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D012717:Sesquiterpenes; C022801:curcumol; D011065:Poly(ADP-ribose) Polymerases; D058539:Phosphatidylinositol 3-Kinase; D053148:Caspase 3
keywords: Apoptosis; Bcl-2; Curcumol; Curcumol (PubChem CID: 160771); Hepatic fibrosis; Nuclear factor-κB; PD 98059 (PubChem CID: 4713); SB-203580 (PubChem CID: 176155); SP600125 (PubChem CID: 8515)