A p53-stabilizing agent, CP-31398, induces p21 expression with increased G2/M phase through the YY1 transcription factor in esophageal carcinoma defective of the p53 pathway

American Journal of Cancer Research

Masato Shingyoji¹  Takao Morinaga²  Thảo Thi Thanh Nguyễn³  Yuji Tada⁴  Boya Zhong⁵  Michiko Hanazono⁶ 

[1] Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan;Department of Pathology, Tokyo Womens Medical University Yachiyo Medical Center, 477-96 Ohwadashinden, Yachiyo, Chiba 276-8524, Japan;Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan;Department of Surgery, School of Medicine, Toho University, 6-11-1 Oomori-nishi, Oota-ku, Tokyo 143-8541, Japan;Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba 260-8717, Japan;Division of Respirology, Chiba Cancer Center, 666-2 Nitona, Chuo-ku, Chiba 260-8717, Japan

关键词: CP-31398;    esophageal carcinoma;    p53;    p21;    YY1;    G2/M arrest;   

DOI  :  

学科分类：肿瘤学

来源: e-Century Publishing Corporation

【 摘 要 】

Restoration of p53 functions is one of the therapeutic strategies for esophageal carcinoma which is often defective of the p53 pathway. We examined effects of CP-31398 which potentially increased expression of wild-type p53 or converted mutated p53 to the wild-type. We used 9 kinds of human squamous esophageal carcinoma cells with different p53 genotypes and examined expression of p53 and the related molecules in CP-31398-treated cells. Cisplatin, a DNA damaging agent, induced cleavages of PARP and caspase-3 without increase of p53 levels, indicating that the p53 down-stream pathway was disrupted in these cells. CP-31398 induced growth retardation but the cytotoxic effects were irrelevant to p53 genotype. CP-31398 influenced expression of p53 and the downstream molecules in a cell-dependent manner, but constantly increased p21 expression at the transcriptional level with decreased YY1 expression. Knockdown experiments with siRNA demonstrated that the CP-31398-mediated p21 up-regulation was unrelated with p53 expression but was associated with YY1 expression. We also showed that CP-31398-induced cell cycle changes including increase of G2/M populations was attributable to the up-regulated p21. These data collectively indicated that CP-31398 augmented endogenous p21 levels and induced cell cycle changes through regulation of YY1, and that YY1 was a novel target of CP-31398 in p53 dysfunctional cells.

【 授权许可】

CC BY-NC