Imperatorin induces Mcl-1 degradation to cooperatively trigger Bax translocation and Bak activation to suppress drug-resistant human hepatoma.
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.
['Li|Xia|X|', 'Zeng|Xueli|X|', 'Sun|Jianguo|J|', 'Li|Hua|H|', 'Wu|Ping|P|', 'Fung|Kwok-Pui|KP|', 'Liu|Feiyan|F|']
D000818:Animals D000972:Antineoplastic Agents, Phytogenic D017209:Apoptosis D006528:Carcinoma, Hepatocellular D049109:Cell Proliferation D004305:Dose-Response Relationship, Drug D019008:Drug Resistance, Neoplasm D011564:Furocoumarins D056945:Hep G2 Cells D006801:Humans D020014:K562 Cells D008113:Liver Neoplasms D008297:Male D051379:Mice D008819:Mice, Nude D064549:Myeloid Cell Leukemia Sequence 1 Protein D046988:Proteasome Endopeptidase Complex D021381:Protein Transport D059748:Proteolysis D015398:Signal Transduction D014162:Transfection D047368:Tumor Burden D020298:U937 Cells D023041:Xenograft Model Antitumor Assays D050998:bcl-2 Homologous Antagonist-Killer Protein D051028:bcl-2-Associated X Protein
Imperatorin Mcl-1 Apoptosis Drug-resistant HepG2 cells