title: p21 induction plays a dual role in anti-cancer activity of ursolic acid.
abstract: Previous studies have shown that induction of G1 arrest and apoptosis by ursolic acid is associated with up-regulation of cyclin-dependent kinase inhibitor (CDKI) protein p21 in multiple types of cancer cells. However, the functional role of p21 induction in G1 cell cycle arrest and apoptosis, and the mechanisms of p21 induction by ursolic acid have not been critically addressed. In the current study, we demonstrated that p21 played a mediator role in G1 cell cycle arrest by ursolic acid, whereas p21-mediated up-regulation of Mcl-1 compromised apoptotic effect of ursolic acid. These results suggest that p21 induction plays a dual role in the anti-cancer activity of ursolic acid in terms of cell cycle and apoptosis regulation. p21 induction by ursolic acid was attributed to p53 transcriptional activation. Moreover, we found that ursolic acid was able to inhibit murine double minute-2 protein (MDM2) and T-LAK cell-originated protein kinase (TOPK), the two negative regulator of p53, which in turn contributed to ursolic acid-induced p53 activation. Our findings provided novel insights into understanding of the mechanisms involved in cell cycle arrest and apoptosis induction in response to ursolic acid exposure.
authors.affiliation: Department of Nutrition and Health, College of Food Science and Nutritional Engineering, Beijing Key Laboratory of Functional Food from Plant Resources, China Agricultural University, Beijing 100083, China Development Center of Science and Technology, Ministry of Agriculture, Beijing 100193, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Nutrition and Health, College of Food Science and Nutritional Engineering, Beijing Key Laboratory of Functional Food from Plant Resources, China Agricultural University, Beijing 100083, China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Nutrition and Health, College of Food Science and Nutritional Engineering, Beijing Key Laboratory of Functional Food from Plant Resources, China Agricultural University, Beijing 100083, China.
authors.forename: Shutao
authors.initials: S
authors.lastname: Yin
authors.affiliation: Department of Nutrition and Health, College of Food Science and Nutritional Engineering, Beijing Key Laboratory of Functional Food from Plant Resources, China Agricultural University, Beijing 100083, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Zhao
authors.affiliation: College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Fan
authors.affiliation: Department of Nutrition and Health, College of Food Science and Nutritional Engineering, Beijing Key Laboratory of Functional Food from Plant Resources, China Agricultural University, Beijing 100083, China hongbo@cau.edu.cn.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Hu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D000097245:Ursolic Acid
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D014315:Triterpenes; D016159:Tumor Suppressor Protein p53; D000097245:Ursolic Acid; C493956:CDKN1A protein, human; C579095:MCL1 protein, human
keywords: MDM2; Mcl-1; TOPK; Ursolic acid; apoptosis; cell cycle; p21; p53