p53-independent induction of G1 arrest and p21WAF1/CIP1 expression by ascofuranone, an isoprenoid antibiotic, through downregulation of c-Myc.
Ascofuranone has been shown to have antitumor activity, but the precise molecular mechanism by which it inhibits the proliferation of cancer cells remains unclear. Here, we study the effects of ascofuranone on cell cycle progression in human cancer cells and find that ascofuranone induces G(1) arrest without cytoxicity with upregulation of p53 and p21(WAF1/CIP1) while downregulating c-Myc and G(1) cyclins. Chromatin immunoprecipitation assay and RNA interference studies with cells deficient in p53 and p21 show that ascofuranone induces p21(WAF1/CIP1) expression and subsequent G(1) arrest through the release of p21(WAF1/CIP1) promoter from c-Myc-mediated transcriptional repression, independent of p53. Ascofuranone-induced p21(WAF1/CIP1) associates with CDK2 and prevents CDK2-cyclin E complex formation, leading to the inactivation of E2F transcriptional activity. These results suggest that ascofuranone upregulates p21(WAF1/CIP1) through p53-independent suppression of c-Myc expression, leading to cytostatic G(1) arrest. Thus, ascofuranone represents a unique natural antitumor compound that targets c-Myc independent of p53.
Jeong
Ji-Hak
JH
Research Institute of Biomedical Engineering and Department of Pathology, Catholic University of Daegu School of Medicine, Nam-gu, Daegu 705-718, Korea.
Kang
Shin-Sung
SS
Park
Kwan-Kyu
KK
Chang
Hyeun-Wook
HW
Magae
Junji
J
Chang
Young-Chae
YC
D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects*; D045325:HCT116 Cells; D056945:Hep G2 Cells; D006801:Humans; D015394:Molecular Structure; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012717:Sesquiterpenes; D016159:Tumor Suppressor Protein p53; C006640:ascofuranone