Adenoviral vector expressing CYLD augments antitumor activity of TRAIL by suppression of NF-kappaB survival signaling in hepatocellular carcinoma.
CYLD is a tumor suppressor gene related to cylindroma and is negative regulator of NF-kappaB. However, antitumor effect of CYLD has not been reported. The activation of NF-kappaB induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) renders hepatocellular carcinoma (HCC) resistant to TRAIL-mediated cell apoptosis. Here we described that the adenoviral vector expressing CYLD (Ad/hTERT-CYLD) augmented the cytotoxicity of TRAIL in HCC cells by negatively regulating NF-kappaB activity since CYLD could reverse the ubiquitination of TNF receptor-associated factor 2 (TRAF2) and interact with the IkappaB kinasegamma (IKKgamma). The combined treatment of Ad/hTERT-CYLD and a conditionally replicating adenovirus carrying TRAIL gene (ZD55-TRAIL) induced rapid and potent apoptosis in HCC cells, characterized by activation of caspase-3, caspase-8, PARP and the reduction of X-linked inhibitor of apoptosis protein (XIAP). In animal study, the combined treatment could eradicate the BEL7404 xenograft tumors. In contrast, treatment with Ad/hTERT-CYLD or ZD55-TRAIL alone achieved less antitumor effect.


CONCLUSIONS
CYLD inhibits TRAIL-mediated NF-kappaB activation and enhances the sensitivity of HCC cells to TRAIL-triggered apoptosis. The combined delivery of Ad/hTERT-CYLD and ZD55-TRAIL may be a new useful strategy for HCC or other tumor cells with enhanced NF-kappaB activity.
Chu
Liang
L
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, PR China.
Gu
Jinfa
J
He
Zhongniu
Z
Xiao
Tian
T
Liu
Xinyuan
X
D000256:Adenoviridae; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D002470:Cell Survival; D000074749:Deubiquitinating Enzyme CYLD; D016147:Genes, Tumor Suppressor; D005822:Genetic Vectors; D006801:Humans; D008113:Liver Neoplasms; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D016328:NF-kappa B; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D025521:Tumor Suppressor Proteins; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD