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.
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.
Hori
Takeshi
T
Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, Toyama 930-0194, Japan.
Kondo
Takashi
T
Kanamori
Masahiko
M
Tabuchi
Yoshiaki
Y
Ogawa
Ryohei
R
Zhao
Qing-Li
QL
Ahmed
Kanwal
K
Yasuda
Taketoshi
T
Seki
Shoji
S
Suzuki
Kayo
K
Kimura
Tomoatsu
T
D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000032:analysis; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D004357:Drug Synergism; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D045726:Metalloproteases / Q000032:analysis; D010879:Piperazines / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D051736:Proto-Oncogene Proteins c-mdm2 / Q000032:analysis; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D015854:Up-Regulation
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007093:Imidazoles; D010879:Piperazines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D045726:Metalloproteases; D053148:Caspase 3