title: Imperatorin induces Mcl-1 degradation to cooperatively trigger Bax translocation and Bak activation to suppress drug-resistant human hepatoma.
abstract: Imperatorin is a small molecule nature compound isolated from the root of Angelica dahurica, and has been shown to exhibit multiple bioeffector functions, including anti-cancer activity. However, the molecular mechanism underlying imperatorin in suppression of tumor growth is unknown. In this study, we aimed at elucidating the molecular mechanisms underlying imperatorin function and determining the efficacy of imperatorin in suppression of drug-resistant human liver cancer. We observed that imperatorin suppresses tumor cell growth through inducing apoptosis, and imperatorin is more effective in induction of multidrug-resistant human liver cancer cells in vitro. We further determined that imperatorin induces apoptosis through both extrinsic and intrinsic apoptosis pathway. At the molecular level, we identified Mcl-1 as the molecular target of imperatorin and determined that imperatorin induces proteosome-dependent Mcl-1 degradation to release Bak and Bax to trigger apoptosis in liver cancer cells. Consistent with its in vitro apoptosis induction activity, imperatorin exhibited potent activity against multidrug-resistant liver cancer xenograft growth in vivo. Taken together, we determined that imperatorin is a Mcl-1 degradation inducer that can effectively suppress multidrug-resistant human liver cancer growth in vivo, and thus holds great promise for development as an effective small molecule anti-cancer agent in human liver cancer therapy to overcome drug resistance.
authors.affiliation: Zhejiang University, Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zijinggang Campus, Hangzhou, PR China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Zhejiang University, Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zijinggang Campus, Hangzhou, PR China.
authors.forename: Xueli
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Zhejiang University, Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zijinggang Campus, Hangzhou, PR China; Zhejiang University, Joint Centre of Zhejiang University and The Chinese University of Hong Kong on Natural Products and Toxicology Research, Zijinggang Campus, Hangzhou, PR China.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Sun
authors.affiliation: Zhejiang University, Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zijinggang Campus, Hangzhou, PR China.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Zhejiang University, Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zijinggang Campus, Hangzhou, PR China; Zhejiang University, Joint Centre of Zhejiang University and The Chinese University of Hong Kong on Natural Products and Toxicology Research, Zijinggang Campus, Hangzhou, PR China; Zhejiang University, The State Key Laboratory of Plant Physiology and Biochemistry, College of Life Sciences, Zijinggang Campus, Hangzhou, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.affiliation: Zhejiang University, Joint Centre of Zhejiang University and The Chinese University of Hong Kong on Natural Products and Toxicology Research, Zijinggang Campus, Hangzhou, PR China; School of Biomedical Sciences (SBS), The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region.
authors.forename: Kwok-Pui
authors.initials: KP
authors.lastname: Fung
authors.affiliation: Zhejiang University, Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zijinggang Campus, Hangzhou, PR China; Zhejiang University, Joint Centre of Zhejiang University and The Chinese University of Hong Kong on Natural Products and Toxicology Research, Zijinggang Campus, Hangzhou, PR China. Electronic address: liuf64@zju.edu.cn.
authors.forename: Feiyan
authors.initials: F
authors.lastname: Liu
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D011564:Furocoumarins / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D020014:K562 Cells; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D021381:Protein Transport; D059748:Proteolysis; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C494772:BAK1 protein, human; C494826:BAX protein, human; D011564:Furocoumarins; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D046988:Proteasome Endopeptidase Complex; C031534:imperatorin
keywords: Apoptosis; Drug-resistant HepG2 cells; Imperatorin; Mcl-1