Abstract
A3 adenosine receptor (A3AR) 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-3β (GSK-3β) was observed. This gave rise to downregulation of β-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 A3AR antagonist MRS 1523 and by the GSK-3β inhibitors lithium and SB216763, confirming that the observed effects were A3AR and GSK-3β mediated. CF101 downregulated PKB/Akt expression level, resulting in a decrease in the level and DNA-binding capacity of NF-κB, 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 A3AR activation induces colon carcinoma growth inhibition via the modulation of the key proteins GSK-3β and NF-κB.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Alt JR, Cleveland JL, Hannink M and Diehl JA . (2000). Genes Dev., 14, 3102–3114.
Chana JS, Grover R, Tulley P, Lohrer H, Sanders R, Grobbelaar AO and Wilson GD . (2002). Br. J. Plast. Surg., 55, 623–627.
Fang X, Yu SX, Lu Y, Bast RC, Woodgett JR and Mills GB . (2000). Proc. Natl. Acad. Sci. USA, 97, 11960–11965.
Ferkey DM and Kimelman D . (2000). Dev. Biol., 225, 471–479.
Fishman P, Bar-Yehuda S, Madi L and Cohn I . (2002a). Anti-cancer Drugs, 13, 1–8.
Fishman P, Bar-Yehuda S, Ohana G, Pathak S, Wasserman L, Barer F and Multani AS . (2001). Exp. Cell Res., 269, 230–236.
Fishman P, Madi L, Bar-Yehuda S, Barer F, Del Valle L and Khalili K . (2002b). Oncogene, 21, 4060–4064.
Fishman P, Bar-Yehuda S, Rath-Wolfson L, Ardon E, Barrer F, Ochaion A and Madi L . (2003). Anticancer Res., 23, 2077–2083.
Gessi S, Varani K, Merighi S, Morelli A, Ferrari D, Leung E, Baraldi PG, Spalluto G and Borea PA . (2001). Br. J. Pharmacol., 134, 116–126.
Hosokawa Y and Arnold A . (1998). Genes Chromosomes Cancer, 22, 66–71.
Ilyas M, Tomlinson A, Rowan M, Pignatelli WF and Bodmer E . (1997). Proc. Natl. Acad. Sci. USA, 94, 10330–10334.
Jain M, Arvanitis C, Chu K, Dewey W, Leonhardt E, Trinh M, Sundberg CD, Bishop JM and Felsher DW . (2002). Science, 297, 63–64.
Joyce D, Albanese C, Steer J, Fu M, Bouzahzah B and Pestell RG . (2001). Cytokine Growth Factor Rev., 12, 73–90.
Karin M, Cao Y, Greten FR and Li ZW . (2002). Nat. Rev. Cancer, 2, 301–310.
Kolligs FT, Bommer G and Goke B . (2002). Digestion, 66, 131–144.
Lovig T, Meling GI, Diep CB, Thorstensen L, Norheim Andersen S, Lothe RA and Rognum TO . (2002). Scand. J. Gastroenterol., 37, 1184–1193.
Madi L, Bar-Yehuda S, Barer F, Ardon E, Ochaion A and Fishman P . (2003). J. Biol. Chem., 278, 42121–42130.
Madrid LV, Mayo MW, Reuther JY and Baldwin AS . (2001). J. Biol. Chem., 276, 18934–18940.
Masuda M, Suzui M, Yasumatu R, Nakashima T, Kuratomi Y, Azuma K, Tomita K, Komiyama S and Weinstein I . (2002). Cancer Res., 62, 3351–3355.
Merighi S, Varani K, Gessi S, Cattabriga E, Iannotta V, Ulouglu C, Leung E and Borea PA . (2001). Br. J. Pharmacol., 134, 1215–1226.
Morin JP . (1999). BioEssays, 21, 1021–1030.
Nguyen DC, Parsa B, Close A, Magnusson B, Crowe DL and Sinha UK . (2003). Int. J. Oncol., 22, 1285–1290.
Ohana G, Bar-Yehuda S, Barer F and Fishman P . (2001). J. Cell. Physiol., 186, 19–23.
Ohana G, Bar-Yehuda S, Arich A, Volfsson-Rat L, Madi L, Dreznick Z, Silberman D, Slosman G and Fishman P . (2003). Br. J. Cancer, 89, 1552–1558.
Olah ME and Stiles GL . (2000). Pharmacol. Ther., 85, 55–75.
Parrella P, Caballero OL, Sidransky D and Merbs SL . (2001). Invest. Ophthalmol. Vis. Sci., 42, 1679–1684.
Poulsen SA and Quinn RJ . (1998). Bioorg. Med. Chem., 6, 619–641.
Schutle G and Fredholm BB . (2002). Mol. Pharmacol., 62, 1137–1146.
Sears R, Nuckolls F, Haura E, Taya Y, Tamai K and Nevins JR . (2000). Genes Dev., 14, 2501–2514.
Suh BC, Kim TD, Lee JU, Seong JK and Kim KT . (2001). Br. J. Pharmacol., 134, 132–142.
Trincavelli ML, Tuscano D, Marroni M, Falleni A, Gremigni V, Ceruti S, Abbracchio MP, Jacobson KA, Cattabeni F and Martini C . (2002a). Mol. Pharmacol., 62, 1373–1384.
Trincavelli ML, Tuscano D, Marroni M, Klotz KN, Lucacchini A and Martini C . (2002b). Biochim. Biophys. Acta, 1591, 55–62.
Van Waardenburg RC, Meijer C, Burger H, Nooter K, De Vries EG, Mulder NH and De Jong S . (1997). Int. J. Cancer, 73, 544–550.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Fishman, P., Bar-Yehuda, S., Ohana, G. et al. An agonist to the A3 adenosine receptor inhibits colon carcinoma growth in mice via modulation of GSK-3β and NF-κB. Oncogene 23, 2465–2471 (2004). https://doi.org/10.1038/sj.onc.1207355
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1207355
Keywords
This article is cited by
-
Purinergic signaling during Marek’s disease in chickens
Scientific Reports (2023)
-
Cancer biology and molecular genetics of A3 adenosine receptor
Oncogene (2022)
-
Extracellular purines, purinergic receptors and tumor growth
Oncogene (2017)
-
The A3 adenosine receptor (A3AR): therapeutic target and predictive biological marker in rheumatoid arthritis
Clinical Rheumatology (2016)
-
Adenosine arrests breast cancer cell motility by A3 receptor stimulation
Purinergic Signalling (2016)