8-Chloro-adenosine sensitizes a human hepatoma cell line to TRAIL-induced apoptosis by caspase-dependent and -independent pathways.

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor (TNF) super-family, induces apoptosis in various cancer cells with little or no effect on normal cells. 8-Chloro-adenosine (8-Cl-Ado) is a potential anti-cancer chemical agent now in clinical trail phase II, though its molecular mechanism remains poorly understood. In the present study, we report that 8-Cl-Ado can promote TRAIL killing activity in the hepatoma cell line BEL-7402 in dose- and time-dependent manner when jointly used in vitro. We showed that the expression of death receptor DR5, but not DR4 was up-regulated and the decoy receptor DcR1 was down-regulated in the cells treated with 8-Cl-Ado and the recombinant soluble TRAIL (rsTRAIL, 95-281 a.a.). Further experiments demonstrated that caspase-family inhibitor z-VAD-fmk prevented the cells from apoptosis induced by co-treatment with 8-Cl-Ado and rsTRAIL for 6 h, however, apoptosis occurred in the cells cultured for 24 h, suggesting that co-treatment induce a caspase-dependent and -independent signaling pathway in the BEL-7402 cells. This phenomenon was confirmed by cleavage analysis of caspase-3 and poly(ADP-ribose) polymerase (PARP), and ROS (reactive oxygen species) assay, respectively. Moreover, transcriptional activity test showed that NF-kappaB was inhibited in the BEL-7402 cells during co-treatment. Our results provided evidence for the first time that 8-Cl-Ado sensitizes the human hepatoma cells BEL-7402 to rsTRAIL-induced apoptosis by up-regulating DR5 expression, inactivating the NF-kappaB activity, and signaling by the caspase-dependent and -independent pathway.

• Authors: Mingjie Wang, Yanxin Liu, Shilian Liu, Dexian Zheng
• Journal: Oncology reports (Oncol Rep) Vol. 12 Issue 1 Pg. 193-9 (Jul 2004) ISSN: 1021-335X [Print] Greece
• PMID: 15201983 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• DNA Primers
• Membrane Glycoproteins
• NF-kappa B
• Recombinant Proteins
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• Tumor Necrosis Factor-alpha
• 2-Chloroadenosine
• Caspases
• 8-chloroadenosine

Topics

• 2-Chloroadenosine (analogs & derivatives, pharmacology)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins
• Base Sequence
• Carcinoma, Hepatocellular
• Caspases (metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• DNA Primers
• Humans
• Membrane Glycoproteins (drug effects, genetics, metabolism)
• NF-kappa B (genetics, metabolism)
• Recombinant Proteins (drug effects, metabolism)
• TNF-Related Apoptosis-Inducing Ligand
• Transfection
• Tumor Necrosis Factor-alpha (drug effects, genetics, metabolism)