title: Triggering Fbw7-mediated proteasomal degradation of c-Myc by oridonin induces cell growth inhibition and apoptosis.
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.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong, PR China.
authors.forename: Hui-Lin
authors.initials: HL
authors.lastname: Huang
authors.forename: Heng-You
authors.initials: HY
authors.lastname: Weng
authors.forename: Lu-Qin
authors.initials: LQ
authors.lastname: Wang
authors.forename: Chun-Hong
authors.initials: CH
authors.lastname: Yu
authors.forename: Qiao-Juan
authors.initials: QJ
authors.lastname: Huang
authors.forename: Pan-Pan
authors.initials: PP
authors.lastname: Zhao
authors.forename: Jun-Zhi
authors.initials: JZ
authors.lastname: Wen
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.forename: Liang-Hu
authors.initials: LH
authors.lastname: Qu
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D044783:F-Box Proteins / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D045786:Diterpenes, Kaurane; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D025801:Ubiquitin; C011959:oridonin; D044767:Ubiquitin-Protein Ligases; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex