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An agonist to the A3 adenosine receptor inhibits colon carcinoma growth in mice via modulation of GSK-3β and NF-κB

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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.

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Authors and Affiliations

  1. Can-Fite Biopharma Ltd, Kiryat-Matalon, Petach-Tikva, 49170, Israel

    Pnina Fishman, Sara Bar-Yehuda, Gil Ohana, Faina Barer, Avivit Ochaion, Abigail Erlanger & Lea Madi

  2. Laboratory of Clinical and Tumor Immunology, The Felsenstein Medical Research Center, Tel-Aviv University Sackler Faculty of Medicine, Rabin Medical Center, Petach-Tikva, Israel

    Pnina Fishman, Sara Bar-Yehuda & Gil Ohana

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  1. Pnina Fishman
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  2. Sara Bar-Yehuda
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  3. Gil Ohana
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  4. Faina Barer
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  5. Avivit Ochaion
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  6. Abigail Erlanger
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  7. Lea Madi
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Correspondence to Pnina Fishman.

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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

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  • DOI: https://doi.org/10.1038/sj.onc.1207355

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