Inhibition of human telomerase reverse transcriptase gene expression by gambogic acid in human hepatoma SMMC-7721 cells.
The activation of human telomerase, a process regulated by the human telomerase reverse transcriptase (hTERT), is a crucial step during cellular immortalization and malignant transformation. We have reported that gambogic acid (GA), a natural product isolated from the gamboge resin of Garcinia hanburyi tree, is an effective telomerase inhibitor and thus displays potent anticancer activity both in vitro and in vivo. Here we present the direct interaction of GA with oncogene c-MYC, a ubiquitous transcription factor involved in the control of cell proliferation and differentiation, as the molecular mechanism of GA's inhibitory effect on telomerase activity. Consistent with the recently reported association between c-MYC overexpression and induction of telomerase activity, we find here that GA treatment of a human hepatoma cell line SMMC-7721 significantly reduced the expression of c-MYC in a time- and concentration-dependent manner accompanied with the down-regulation of the hTERT transcription and the ultimate reduction in telomerase activity. Our results indicate that the hTERT is a target of c-MYC activity and identify a feasible mechanism of GA's potent anticancer activity.
Guo
Qing-Long
QL
Department of Physiology, China Pharmaceutical University, 24 Tongjiaxian, Nanjing 210009, China. qinglongguo@hotmail.com
Lin
Sen-Sen
SS
You
Qi-Dong
QD
Gu
Hong-Yan
HY
Yu
Jun
J
Zhao
Li
L
Qi
Qi
Q
Liang
Fei
F
Tan
Zi
Z
Wang
Xiaotang
X
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000235:genetics*; D044004:Xanthones / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D004268:DNA-Binding Proteins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D044004:Xanthones; C052659:gambogic acid; D019098:Telomerase