Phytosphingosine in combination with TRAIL sensitizes cancer cells to TRAIL through synergistic up-regulation of DR4 and DR5.
Sensitization of cancer cells to TRAIL could improve the effectiveness of TRAIL as an anticancer agent. We explored whether TRAIL in combination with phytosphingosine could sensitize cancer cells to TRAIL. The combined treatment enhanced synergistic apoptotic cell death of Jurkat T cells, compared to TRAIL or phytosphingosine alone. Enhanced apoptosis in response to the combination treatment was associated with caspase-8 activation-mediated Bax and Bak activation and mitochondrial dysfunction. The combination treatment also resulted in synergistic up-regulation of TRAIL receptor R1 (DR4) and R2 (DR5). siRNA targeting of DR5 significantly attenuated the combination treatment-induced caspase-8 activation, mitochondrial dysfunction, and apoptotic cell death. Upon stimulation of cells with the combination treatment, NF-kappaB was activated. Moreover, siRNA targeting of NF-kappaB significantly attenuated the combination treatment-induced DR4 and DR5 expression and receptor-mediated caspase-8 activation. These results indicate that phytosphingosine sensitizes cancer cells to TRAIL through the synergistic up-regulation of DR4 and DR5 in an NF-kappaB-dependent fashion resulting in caspase-8 activation and subsequent mitochondrial dysfunction. These findings support the potential application of combination treatment with TRAIL and phytosphingosine in the treatment of cancers that are less sensitive to TRAIL.
Choi
Soon-Young
SY
Laboratory of Radiation Experimental Therapeutics, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Korea.
Kim
Min-Jung
MJ
Chung
Hee Yong
HY
Lee
Su-Jae
SJ
Jang
Young-Ju
YJ
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053181:Caspase 8 / Q000378:metabolism; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis* / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis* / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494772:BAK1 protein, human; C494826:BAX protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D016328:NF-kappa B; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D053181:Caspase 8; C012491:phytosphingosine; D013110:Sphingosine