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Suppression of c-Myc enhances p21 WAF1/CIP1 -mediated G1 cell cycle arrest through the modulation of ERK phosphorylation by ascochlorin

Suppression of c-Myc enhances p21 WAF1/CIP1 -mediated G1 cell cycle arrest through the modulation of ERK phosphorylation by ascochlorin

Yun-Jeong Jeong, Hyang-Sook Hoe, Hyun-Ji Cho, Kwan-Kyu Park, Dae-Dong Kim, Cheorl-Ho Kim, Junji Magae, Dong Wook Kang, Sang-Rae Lee, Young-Chae Chang

J Cell Biochem. 2018 Feb;119(2):2036-2047.

PMID: 28833404

Abstract:

Numerous anti-cancer agents inhibit cell cycle progression via a p53-dependent mechanism; however, other genes such as the proto-oncogene c-Myc are promising targets for anticancer therapy. In the present study, we provide evidence that ascochlorin, an isoprenoid antibiotic, is a non-toxic anti-cancer agent that induces G1 cell cycle arrest and p21WAF1/CIP1 expression by downregulating of c-Myc protein expression. Ascochlorin promoted the G1 arrest, upregulated p53 and p21WAF1/CIP1 , and downregulated c-Myc in HCT116 cells. In p53-deficient cells, ascochlorin enhanced the expression of G1 arrest-related genes except p53. Small interfering RNA (siRNA) mediated c-Myc silencing indicated that the transcriptional repression of c-Myc was related to ascochlorin-mediated modulation of p21WAF1/CIP1 expression. Ascochlorin suppressed the stabilization of the c-Myc protein by inhibiting ERK and P70S6K/4EBP1 phosphorylation, whereas it had no effect on c-Myc degradation mediated by PI3K/Akt/GSK3β. The ERK inhibitor PD98059 and siRNA-mediated ERK silencing induced G1 arrest and p21WAF1/CIP1 expression by downregulating c-Myc in p53-deficient cells. These results indicated that ascochlorin-induced G1 arrest is associated with the repression of ERK phosphorylation and c-Myc expression. Thus, we reveal a role for ascochlorin in inhibiting tumor growth via G1 arrest, and identify a novel regulatory mechanism for ERK/c-Myc.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP26166392	Ascochlorin		26166-39-2	Price

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