title: Human hepatocellular carcinoma cells resist to TRAIL-induced apoptosis, and the resistance is abolished by cisplatin.
abstract: TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF family, selectively induce apoptosis in various transformed cell lines but not in almost-normal tissues. It is regulated by 2 death receptors, TRAIL receptor 1 (TRAIL-R1) and TRAIL-R2 and 2 decoy receptors, TRAIL-R3 and TRAIL-R4. However, the determining factors of the sensitivity to TRAIL-induced apoptosis are not clearly understood. Herein, we investigated the expression of TRAIL-R, c-FLIP, FADD-like interleukin-1beta-converting enzyme inhibitory protein, and TRAIL-induced apoptosis in human hepatocellular carcinoma (HCC) cell lines. Seven of ten HCC cell lines showed resistance to TRAIL-induced apoptosis and five of seven TRAIL-resistant cell lines became sensitive to TRAIL by co-treatment with cycloheximide. In HCC cell lines, their TRAIL resistance did not correlate with the basal expression level of TRAIL receptors or c-FLIP, however, in human tissues, TRAIL-R1 and TRAIL-R2 expressions were notably decreased compared to normal counterpart. Cisplatin showed synergistic effect on TRAIL-induced apoptosis in most HCC cell lines regardless of their p53 status and TRAIL-R1 was induced by cisplatin treatment in certain cell lines. Inhibition of nuclear factor K B (NF-kappaB) by SN50, a peptide inhibitor of NF-KB activity, had no effect on TRAIL-induced apoptosis in HCC cells. These results suggest that (a) the majority of human HCC cell lines are resistant to TRAIL-induced apoptosis and cycloheximide-sensitive short-lived antiapoptotic molecule(s) is responsible for this resistance, (b) the expression of TRAIL-R1 and TRAIL-R2 is reduced in HCC tissues, and the increased expression of TRAIL-R1 may be a mechanism of cisplatininduced sensitization to TRAIL-induced apoptosis in some HCC cells, and (c) the activation of NF-kappaB may not be involved in the TRAIL resistance of HCC cells
authors.affiliation: Department of Microbiology, Institute for Immunology and Immunological Diseases, Deajeon, Korea.
authors.forename: Eui-Cheol
authors.initials: EC
authors.lastname: Shin
authors.forename: Young Rim
authors.initials: YR
authors.lastname: Seong
authors.forename: Chul Hoon
authors.initials: CH
authors.lastname: Kim
authors.forename: Hoguen
authors.initials: H
authors.lastname: Kim
authors.forename: Young Soo
authors.initials: YS
authors.lastname: Ahn
authors.forename: Kunhong
authors.initials: K
authors.lastname: Kim
authors.forename: Se Jong
authors.initials: SJ
authors.lastname: Kim
authors.forename: Seung-Suh
authors.initials: SS
authors.lastname: Hong
authors.forename: Jeon Han
authors.initials: JH
authors.lastname: Park
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology*; D003513:Cycloheximide / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010455:Peptides; D018124:Receptors, Tumor Necrosis Factor; C118258:SN50 peptide; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide; D002945:Cisplatin