Calyculin A causes sensitization to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by ROS-mediated down-regulation of cellular FLICE-inhibiting protein (c-FLIP) and by enhancing death receptor 4 mRNA stabilization.
Calyculin A (Cal A) is a serine/threonine phosphatase inhibitor that is capable of inducing apoptosis in cancer cells. In this study, we examined whether Cal A could modulate TRAIL-induced apoptosis in human renal carcinoma-derived Caki cells. Our results show that Cal A is capable of sensitizing Caki cells to TRAIL-induced apoptosis, as well as U2OS human osteosarcoma cells and A549 human lung adenocarcinoma epithelial cells. Cal A increases intracellular ROS production and down-regulates c-FLIP(L) expression. Interestingly, the down-regulation of protein phosphatase 1 (PP1) by PP1 siRNA also reduced c-FLIP(L) expression via reactive oxygen species production. Furthermore, Cal A induced death receptor 4 (DR4) mRNA and protein expression by enhancing DR4 mRNA stability. We also found that PP4 siRNA up-regulated DR4 mRNA and protein expression. Collectively, our results suggest that Cal A could enhance TRAIL-mediated apoptosis via the down-regulation of c-FLIP(L) and the up-regulation of DR4 in human renal cell carcinoma cell line Caki.
Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea.
Seon Min
SM
Woo
Kyoung-jin
KJ
Min
Taeg Kyu
TK
Kwon
D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008387:Marine Toxins; D008954:Models, Biological; D010080:Oxazoles / Q000494:pharmacology*; D054645:Protein Phosphatase 1 / Q000378:metabolism; D020871:RNA Stability / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D008387:Marine Toxins; D010080:Oxazoles; D017382:Reactive Oxygen Species; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C059041:calyculin A; D054645:Protein Phosphatase 1