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Mol Cancer Ther. 2012 May;11(5):1155-65. doi: 10.1158/1535-7163.MCT-12-0066. Epub 2012 Mar 2.

Triggering Fbw7-mediated proteasomal degradation of c-Myc by oridonin induces cell growth inhibition and apoptosis.

Author information

1
Key Laboratory of Gene Engineering of the Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong, PR China.

Abstract

The transcription factor c-Myc is important in cell fate decisions and is frequently overexpressed in cancer cells, making it an attractive therapeutic target. Natural compounds are among the current strategies aimed at targeting c-Myc, but their modes of action still need to be characterized. To explore the mechanisms underlying the anticancer activity of a natural diterpenoid, oridonin, we conducted miRNA expression profiling and statistical analyses that strongly suggested that c-Myc was a potential molecular target of oridonin. Furthermore, experimental data showed that oridonin significantly reduced c-Myc protein levels in vitro and in vivo and that this reduction was mediated by the ubiquitin-proteasome system. Fbw7, a component of the ubiquitin-proteasome system and an E3 ubiquitin ligase of c-Myc, was upregulated rapidly in K562 cells and other leukemia and lymphoma cells, resulting in the rapid turnover of c-Myc. In cell lines harboring mutations in the WD domain of Fbw7, the degradation of c-Myc induced by oridonin was attenuated during short-term treatment. GSK-3, an Fbw7 priming kinase, was also activated by oridonin, along with an increase in T58-phosphorylated c-Myc. Furthermore, the knockdown of Fbw7 or the forced expression of stable c-Myc resulted in reduced sensitization to oridonin-induced apoptosis. Our observations help to clarify the anticancer mechanisms of oridonin and shed light on the application of this natural compound as an Fbw7-c-Myc pathway targeting agent in cancer treatment.

PMID:
22389469
DOI:
10.1158/1535-7163.MCT-12-0066
[Indexed for MEDLINE]
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