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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects*
  • Cell Cycle Proteins / metabolism*
  • Cell Proliferation / drug effects
  • Diterpenes, Kaurane / pharmacology*
  • Enzyme Activation / drug effects
  • F-Box Proteins / metabolism*
  • F-Box-WD Repeat-Containing Protein 7
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glycogen Synthase Kinase 3 / metabolism
  • HL-60 Cells
  • Humans
  • K562 Cells
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • MicroRNAs / genetics
  • Phosphorylation / drug effects
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Stability / drug effects
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Signal Transduction / drug effects
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Antineoplastic Agents, Phytogenic
  • Cell Cycle Proteins
  • Diterpenes, Kaurane
  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • MicroRNAs
  • Proto-Oncogene Proteins c-myc
  • Ubiquitin
  • oridonin
  • Ubiquitin-Protein Ligases
  • Glycogen Synthase Kinase 3
  • Proteasome Endopeptidase Complex