Curcumin suppresses proliferation and induces apoptosis of human hepatocellular carcinoma cells via the wnt signaling pathway.
Curcumin from the rhizome of Curcuma longa (zingiberaceae) has been reported to be a chemopreventive agent that affects cell proliferation by arresting the cell cycle in G2 and modulating the wnt signaling pathway. We found that curcumin inhibits proliferation and induces apoptosis of human hepatocellular carcinoma (HCC) cells in a concentration-dependent manner. We identified that curcumin interrupts wnt signaling by decreasing β-catenin activity, which in turn suppresses the expression of β-catenin target genes (c-myc, VEGF and cyclin D1). Our results from molecular simulation of curcumin binding to Dvl2 protein and from binding free energy calculations suggest that curcumin may prevent axin recruitment to cellular membrane in order to maintain the functional β-catenin destruction complex in normal cells. This results in β-catenin being unable to accumulate in the nucleus, depriving the protein of its ability to bind with lymphoid enhancer factor/T cell-specific transcription factor (Lef/Tcf) and repressing its activation of target gene transcription. This may be one mechanism through which curcumin inhibits proliferation and induces apoptosis of HCC cells.
Department of Pharmacology, Basic Medical College, Zhengzhou University, Zhengzhou 450001, P.R. China.
Marvin Xuejun
MX
Xu
Linlin
L
Zhao
Chaoyang
C
Deng
Lu
L
Yang
Yang
Y
Wang
Tao
T
Guo
Lifang
L
Li
Jianping
J
Lin
Lirong
L
Zhang
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D060466:Axin Protein / Q000378:metabolism; D060465:Axin Signaling Complex / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D019938:Cyclin D1 / Q000096:biosynthesis; D000072261:Dishevelled Proteins; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D062105:Molecular Docking Simulation; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D051820:TCF Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D060466:Axin Protein; D060465:Axin Signaling Complex; C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; D004791:Enzyme Inhibitors; C489427:MYC protein, human; D010750:Phosphoproteins; D016271:Proto-Oncogene Proteins c-myc; D051820:TCF Transcription Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1; D003474:Curcumin