https://scholars.lib.ntu.edu.tw/handle/123456789/368808
標題: | Aciculatin induces p53-dependent apoptosis via MDM2 depletion in human cancer cells in vitro and in vivo | 作者: | CHE-MING TENG | 公開日期: | 2012 | 卷: | 7 | 期: | 8 | 來源出版物: | PLoS ONE | 摘要: | Aciculatin, a natural compound extracted from the medicinal herb Chrysopogon aciculatus, shows potent anti-cancer potency. This study is the first to prove that aciculatin induces cell death in human cancer cells and HCT116 mouse xenografts due to G1 arrest and subsequent apoptosis. The primary reason for cell cycle arrest and cell death was p53 accumulation followed by increased p21 level, dephosphorylation of Rb protein, PUMA expression, and induction of apoptotic signals such as cleavage of caspase-9, caspase-3, and PARP. We demonstrated that p53 allele-null (-/-) (p53-KO) HCT116 cells were more resistant to aciculatin than cells with wild-type p53 (+/+). The same result was achieved by knocking down p53 with siRNA in p53 wild-type cells, indicating that p53 plays a crucial role in aciculatin-induced apoptosis. Although DNA damage is the most common event leading to p53 activation, we found only weak evidence of DNA damage after aciculatin treatment. Interestingly, the aciculatin-induced downregulation of MDM2, an important negative regulator of p53, contributed to p53 accumulation. The anti-cancer activity and importance of p53 after aciculatin treatment were also confirmed in the HCT116 xenograft models. Collectively, these results indicate that aciculatin treatment induces cell cycle arrest and apoptosis via inhibition of MDM2 expression, thereby inducing p53 accumulation without significant DNA damage and genome toxicity. ? 2012 Lai et al. |
URI: | http://www.scopus.com/inward/record.url?eid=2-s2.0-84865050263&partnerID=MN8TOARS http://scholars.lib.ntu.edu.tw/handle/123456789/368808 |
DOI: | 10.1371/journal.pone.0042192 | SDG/關鍵字: | aciculatin; antineoplastic agent; caspase 3; caspase 9; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; protein MDM2; protein p21; protein p53; PUMA protein; retinoblastoma protein; small interfering RNA; unclassified drug; animal experiment; animal model; animal tissue; antineoplastic activity; article; bioaccumulation; cancer cell culture; cancer chemotherapy; cell cycle arrest; colorectal cancer; controlled study; DNA damage; down regulation; drug cytotoxicity; drug effect; drug structure; enzyme activity; gene frequency; human; human cell; in vitro study; in vivo study; male; mouse; nonhuman; protein dephosphorylation; protein expression; protein function; signal transduction; tumor suppressor gene; tumor xenograft; upregulation; wild type; Animals; Antineoplastic Agents; Apoptosis; Caspases; Cell Cycle Checkpoints; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21; Enzyme Induction; Flavonoids; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Male; Mice; Proteasome Endopeptidase Complex; Proteolysis; Proto-Oncogene Proteins c-mdm2; Transcription, Genetic; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays |
顯示於: | 醫學系 |
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