An agonist to the A3 adenosine receptor inhibits colon carcinoma growth in mice via modulation of GSK-3 beta and NF-kappa B.
A(3) adenosine receptor (A(3)AR) activation with the specific agonist CF101 has been shown to inhibit the development of colon carcinoma growth in syngeneic and xenograft murine models. In the present study, we looked into the effect of CF101 on the molecular mechanisms involved in the inhibition of HCT-116 colon carcinoma in mice. In tumor lesions derived from CF101-treated mice, a decrease in the expression level of protein kinase A (PKA) and an increase in glycogen synthase kinase-3 beta (GSK-3 beta) was observed. This gave rise to downregulation of beta-catenin and its transcriptional gene products cyclin D1 and c-Myc. Further mechanistic studies in vitro revealed that these responses were counteracted by the selective A(3)AR antagonist MRS 1523 and by the GSK-3 beta inhibitors lithium and SB216763, confirming that the observed effects were A(3)AR and GSK-3 beta mediated. CF101 downregulated PKB/Akt expression level, resulting in a decrease in the level and DNA-binding capacity of NF-kappa B, both in vivo and in vitro. Furthermore, the PKA and PKB/Akt inhibitors H89 and Worthmannin mimicked the effect of CF101, supporting their involvement in mediating the response to the agonist. This is the first demonstration that A(3)AR activation induces colon carcinoma growth inhibition via the modulation of the key proteins GSK-3 beta and NF-kappa B.
Fishman
Pnina
P
Can-Fite Biopharma Ltd, Kiryat-Matalon, Petach-Tikva 49170, Israel. pnina@canfite.co.il
Bar-Yehuda
Sara
S
Ohana
Gil
G
Barer
Faina
F
Ochaion
Avivit
A
Erlanger
Abigail
A
Madi
Lea
L
D000241:Adenosine / Q000819:agonists* / Q000031:analogs & derivatives / Q000627:therapeutic use; D000818:Animals; D002277:Carcinoma / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D019938:Cyclin D1 / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008094:Lithium / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000187:drug effects; D058906:Purinergic P1 Receptor Agonists; D011725:Pyridines / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism; D051176:beta Catenin
C419146:2,3-diethyl-4,5-dipropyl-6-phenylpyridine-3-thiocarboxylate-5-carboxylate; C478920:CF101; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D006131:Growth Inhibitors; D007211:Indoles; D008301:Maleimides; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; D058906:Purinergic P1 Receptor Agonists; D011725:Pyridines; C417521:SB 216763; D015534:Trans-Activators; D051176:beta Catenin; D019938:Cyclin D1; D008094:Lithium; D000071679:Glycogen Synthase Kinase 3 beta; D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D000241:Adenosine