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: Xia Li, Xueli Zeng, Jianguo Sun, Hua Li, Ping Wu, Kwok-Pui Fung, Feiyan Liu
• Journal: Cancer letters (Cancer Lett) Vol. 348 Issue 1-2 Pg. 146-55 (Jun 28 2014) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 24680709 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents, Phytogenic
• BAK1 protein, human
• BAX protein, human
• Furocoumarins
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• bcl-2 Homologous Antagonist-Killer Protein
• bcl-2-Associated X Protein
• Proteasome Endopeptidase Complex
• imperatorin

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Hepatocellular (drug therapy, genetics, metabolism, pathology)
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm (drug effects)
• Furocoumarins (pharmacology)
• Hep G2 Cells
• Humans
• K562 Cells
• Liver Neoplasms (drug therapy, genetics, metabolism, pathology)
• Male
• Mice
• Mice, Nude
• Myeloid Cell Leukemia Sequence 1 Protein (genetics, metabolism)
• Proteasome Endopeptidase Complex (metabolism)
• Protein Transport
• Proteolysis
• Signal Transduction (drug effects)
• Transfection
• Tumor Burden (drug effects)
• U937 Cells
• Xenograft Model Antitumor Assays
• bcl-2 Homologous Antagonist-Killer Protein (metabolism)
• bcl-2-Associated X Protein (metabolism)