Reference - Detail
RRC ID | 18922 |
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Author | Hori T, Kondo T, Kanamori M, Tabuchi Y, Ogawa R, Zhao QL, Ahmed K, Yasuda T, Seki S, Suzuki K, Kimura T. |
Title | Nutlin-3 enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through up-regulation of death receptor 5 (DR5) in human sarcoma HOS cells and human colon cancer HCT116 cells. |
Journal | Cancer Lett |
Abstract |
MDM2 is a critical negative regulator of the p53 tumor suppressor protein. Recently, nutlins, small-molecule antagonists of MDM2, have been developed to inhibit the p53-MDM2 interaction and activate p53 signaling. The expressions of DR4 and DR5, Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptors, are regulated by p53. In this study, the combined effects of nutlin-3 and TRAIL on apoptosis were investigated in HOS and HCT116 cells, which express wild-type p53. Nutlin-3 and TRAIL synergistically enhanced apoptosis owing to their intrinsic and extrinsic pathway signals, respectively. The increase in the Bid expression level and the decrease in the expression levels of anti-apoptotic proteins, c-FLIP and XIAP, were involved in this apoptosis enhancement. Furthermore, nutlin-3 activated the DR5 promoter and increased the expression levels of DR5 at mRNA and protein levels. These results indicate that the combination, treated with nutlin-3 and TRAIL, is useful for apoptosis induction in malignant cells expressing wild-type p53. |
Volume | 287(1) |
Pages | 98-108 |
Published | 2010-1-1 |
DOI | 10.1016/j.canlet.2009.06.002 |
PII | S0304-3835(09)00406-6 |
PMID | 19577358 |
MeSH | Apoptosis / drug effects* CASP8 and FADD-Like Apoptosis Regulating Protein / analysis Caspase 3 / metabolism Cell Survival / drug effects Colonic Neoplasms / drug therapy* Colonic Neoplasms / pathology Cyclin-Dependent Kinase Inhibitor p21 / analysis Drug Synergism HCT116 Cells Humans Imidazoles / pharmacology* Metalloproteases / analysis Piperazines / pharmacology* Promoter Regions, Genetic Proto-Oncogene Proteins c-mdm2 / analysis Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics* Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism TNF-Related Apoptosis-Inducing Ligand / pharmacology* Tumor Suppressor Protein p53 / analysis Up-Regulation |
IF | 7.36 |
Times Cited | 34 |
WOS Category | ONCOLOGY |
Resource | |
Human and Animal Cells | HOS(RCB0992) |