Ascochlorin, an isoprenoid antibiotic, induces G1 arrest via downregulation of c-Myc in a p53-independent manner.
Numerous anti-cancer agents inhibit cell cycle progression via a p53-dependent mechanism; however, many of these carcinostatic substances are toxic. Here, we show that ascochlorin, an isoprenoid antibiotic, is a non-toxic anti-cancer agent that induces G1 arrest via the induction of p21(WAF1/CIP1) in a c-Myc, but not a p53, dependent manner. Ascochlorin has a broad spectrum of anti-tumor and anti-metastatic activities, but the molecular mechanism by which it inhibits cell cycle progression of cancer cells remains to be elucidated. We demonstrated that cytostatic G1 arrest by ascochlorin is mainly associated with the upregulation of p21(WAF1/CIP1), and the downregulation of c-Myc. Furthermore, we used a chromatin immunoprecipitation assay, RNA interference, and p53-deficient cells to verify that p21(WAF1/CIP1) induction by ascochlorin is related to transcriptional repression of c-Myc. Ascochlorin abolished pRB hyperphosphorylation, which resulted in the inactivation of E2F transcriptional activity. These results suggest that ascochlorin induces G1 arrest via the p53-independent suppression of c-Myc. Thus, we reveal a role for ascochlorin in inhibiting tumor growth via G1 arrest, and identify a novel regulatory mechanism for c-Myc.
Jeong
Ji-Hak
JH
Research Institute of Biomedical Engineering and Department of Pathology, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea.
Chang
Young-Chae
YC
D000475:Alkenes / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015536:Down-Regulation; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D010636:Phenols / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000475:Alkenes; D000903:Antibiotics, Antineoplastic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C489427:MYC protein, human; D010636:Phenols; D016271:Proto-Oncogene Proteins c-myc; D013729:Terpenes; D016159:Tumor Suppressor Protein p53; C415745:ascochlorin