Targeting the A3 adenosine receptor for cancer therapy: inhibition of prostate carcinoma cell growth by A3AR agonist.
BACKGROUND
Agonists to A3 adenosine receptor (A3AR) were shown to inhibit the growth of various tumor cell types. The present study demonstrates that a synthetic A3AR agonist, 1-deoxy-1-[6-[[(3-iodophenyl)methyl]amino]-9H-purine- 9-yl]-N-methyl-beta-D-ribofura-nuronamide (IB-MECA), inhibits the growth of androgen-independent PC-3 prostate human carcinoma cells and illustrates the molecular mechanism involved.


METHODS
PC-3 prostate carcinoma cells were used. Cell growth was examined in vitro by the thymidine incorporation assay and in vivo by inoculating the tumor cells subcutaneously into nude mice and monitoring tumor size. The protein expression level in cells and tumor extracts was tested by Western blot analysis.


RESULTS
A decrease in the protein expression level of A3AR and the downstream effector PKAc was observed. Consequently, the GSK-3 beta protein level increased, resulting in the destabilization of beta-catenin and the subsequent suppression of cyclin D1 and c-myc expression. IB-MECA treatment also induced down-modulation of the expression of NF-kappa B/p65, known to regulate the transcription of cyclin D1 and c-Myc. This chain of events occurred both in vitro and in vivo and suggests the use of the above-mentioned signaling proteins as markers to predict tumor cell response to A3AR activation.


CONCLUSIONS
Taken together, we demonstrated that A3AR activation deregulates the Wnt and the NF-kappa B signaling pathways resulting in the inhibition of prostate carcinoma cell growth.
Fishman
Pnina
P
Can-Fite Biopharma Ltd, Kiryat-Matalon, Laboratory of Clinical and Tumor Immunology, Felsenstein Medical Research Center, Tel-Aviv University Sackler Faculty of Medicine, Rabin Medical Center, Petach-Tikva, Israel. pfishman@post.tau.ac.il
Bar-Yehuda
Sara
S
Ardon
Eti
E
Rath-Wolfson
Lea
L
Barrer
Faina
F
Ochaion
Avivit
A
Madi
Lea
L
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis; D019938:Cyclin D1 / Q000096:biosynthesis; D003598:Cytoskeletal Proteins / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D058906:Purinergic P1 Receptor Agonists; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000096:biosynthesis / Q000235:genetics; D015534:Trans-Activators / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin
D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D006131:Growth Inhibitors; D016328:NF-kappa B; D058906:Purinergic P1 Receptor Agonists; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; D015534:Trans-Activators; D051176:beta Catenin; D019938:Cyclin D1; C084956:N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine; D017868:Cyclic AMP-Dependent Protein Kinases; D000241:Adenosine