The coffee diterpene kahweol sensitizes TRAIL-induced apoptosis in renal carcinoma Caki cells through down-regulation of Bcl-2 and c-FLIP.
Kahweol, a coffee-specific diterpene, found in the beans of Coffea arabica, has potent anti-carcinogenic, anti-tumor, and anti-inflammatory properties. TRAIL is a potential anti-cancer compound that induces apoptosis in a wide variety of cancer cells, but not in most normal human cell types. In the present study, we show that kahweol sensitizes human renal cancer cells, but not normal human mesangial cells, to TRAIL-mediated apoptosis. Moreover, treatment with a combination of kahweol and TRAIL induces significant apoptosis in various cancer cell types, thus presenting an attractive novel strategy for cancer treatment. Our experiments show that treatment with a combination of kahweol and TRAIL-induced apoptosis, and stimulated of DEVDase activity, DNA fragmentation, and cleavage of PARP, which was prevented by pretreatment with z-VAD, indicative of cell death via a caspase-dependent pathway. Kahweol-induced down-regulation of Bcl-2 and ectopic expression of Bcl-2 led to attenuation of kahweol plus TRAIL-mediated apoptosis, indicative of Bcl-2 involvement in the apoptotic process. In addition, the c-FLIP and caspase signal pathways seem to play a crucial role in apoptosis triggered by the combination of kahweol and TRAIL in Caki cells. Our results collectively demonstrate that down-regulation of Bcl-2 and c-FLIP contributes to the sensitizing effect of kahweol on TRAIL-mediated apoptosis in cancer cells.
Um
Hee Jung
HJ
Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu, South Korea.
Oh
Jung Hwa
JH
Kim
Yoon-Nyun
YN
Choi
Yung Hyun
YH
Kim
Sang Hyun
SH
Park
Jong-Wook
JW
Kwon
Taeg Kyu
TK
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D002277:Carcinoma / Q000188:drug therapy*; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D003069:Coffee / Q000737:chemistry; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy*; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D003069:Coffee; D004224:Diterpenes; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C053401:kahweol; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases