Cl-IB-MECA enhances TRAIL-induced apoptosis via the modulation of NF-kappaB signalling pathway in thyroid cancer cells.

Abstract

Apoptosis is an endogenous process that can be a useful anti-cancer tool. This study aimed to investigate the effect of Cl-IB-MECA, adenosine receptor A3 agonist, on TRAIL-induced apoptosis of thyroid carcinoma cells. Cl-IB-MECA enhanced TRAIL-mediated apoptosis in FRO but not in ARO cells. This effect was correlated to higher expression levels of DR5 on FRO than ARO cells, that instead presented higher levels of decoy receptors, DcR1 and DcR2. To understand the cross-talk between the effect of Cl-IB-MECA and TRAIL, we evaluated the nuclear translocation of p65 and c-Rel. Since the dependency by NF-kappaB, TRAIL promoted the nuclear translocation of both p65 and c-Rel subunits. However, the addition of Cl-IB-MECA led to the predominant translocation of c-Rel after TRAIL addition. Furthermore, Bcl-2, cFLIP and pAkt were lower induced than caspase-3 and -9 in FRO cells. To discriminate a specific effect of TRAIL, we used tumour necrosis factor-alpha (TNF-alpha) with Cl-IB-MECA. In this case, no synergism was observed. In addition, the effect of Cl-IB-MECA was not A3 receptor-dependent since its antagonists, MRS1191 and FA385, failed to block Cl-IB-MECA activity on TRAIL-treated FRO cells. In conclusion, Cl-IB-MECA enhanced TRAIL-mediated apoptosis via NF-kappaB/c-Rel activation and DR5-dependent manner. This study may shed light on a potential drug cocktail that may prove useful as anti-cancer in an in vivo animal model.

• Authors: Silvana Morello, Rosalinda Sorrentino, Amalia Porta, Giovanni Forte, Ada Popolo, Antonello Petrella, Aldo Pinto
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 221 Issue 2 Pg. 378-86 (Nov 2009) ISSN: 1097-4652 [Electronic] United States
• PMID: 19562684 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adenosine A3 Receptor Antagonists
• CASP8 and FADD-Like Apoptosis Regulating Protein
• CFLAR protein, human
• NF-kappa B
• Proto-Oncogene Proteins c-bcl-2
• Proto-Oncogene Proteins c-rel
• Receptor, Adenosine A3
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNF-Related Apoptosis-Inducing Ligand
• Tumor Necrosis Factor-alpha
• Proto-Oncogene Proteins c-akt
• Adenosine
• 2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide

Topics

• Adenosine (analogs & derivatives, pharmacology)
• Adenosine A3 Receptor Antagonists
• Apoptosis (drug effects)
• CASP8 and FADD-Like Apoptosis Regulating Protein (metabolism)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Humans
• NF-kappa B (metabolism)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Proto-Oncogene Proteins c-rel (metabolism)
• Receptor, Adenosine A3 (metabolism)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (metabolism)
• Signal Transduction (drug effects)
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• Thyroid Neoplasms (enzymology, metabolism, pathology)
• Tumor Necrosis Factor-alpha (pharmacology)