Introduction: Adenosine-based drugs have shown promising results against various solid tumors including prostate cancer. These drugs exert their effects via adenosine receptors (ARs), and in prostate cancer, the A3AR subtype appears to play a major role in its anti-tumor action. MicroRNAs (miRs) are small non-coding RNAs that regulate the coding RNAs at post-transcriptional level. One of these, miR-21, has been shown to promote prostate cancer growth and invasiveness. In the present study, we hypothesized that A3AR agonists suppressed prostate tumor growth by reducing miR-21 expression. Methods: In vivo studies were performed in xenograft model of prostate cancer in severe combined immunodeficient (SCID) mice. Mice were injected subcutaneously with PC3-MM human prostate cancer cells, treated with vehicle, the agonist N’-(3-iodobenzyl) adenosine-5′-N-methyluronamide (IB-MECA), the antagonist 9-Chloro-2-(2-furanyl)-5-((phenylacetyl)amino)-[1,2,4]triazolo[1,5-c]quinazoline (MRS1220) or MRS1220 + IB-MECA, on alternate day for 2-3 weeks, and tumor growth was measured. Primary tumors were then excised and used to determine miR-21 (by TaqMan assay) and maspin, PDCD4 and TPM1 (by Western blotting and RT-PCR). In vitro studies were done in PC3-MM cells grown in cell culture plates. The levels of miR-21 were also detected in RNA samples obtained from human prostate cancer tissues (OriGene Technologies), while the levels of maspin and PDCD4 were determined in the formalin-fixed paraffin-embedded (FFPE) prostate tumor sections by immunohistochemistry. Results: IB-MECA suppressed tumor growth in SCID mice. This effect was blunted in presence of the antagonist, MRS1220. Reductions in tumor volume were associated with reduced expression of miR-21 in the primary tumors. Furthermore, we observed up-regulation of the tumor suppressor proteins maspin, PDCD4 and TPM1, which are known to be negatively regulated by miR-21. Similar findings were obtained in in vitro cell culture studies. In human prostate cancer RNA samples from patients with different stages of prostate cancer there was high expression of miR-21. This finding co-related with down-regulation of its target proteins, maspin and PDCD4, in human prostate tumor sections. Conclusions: Based on the data, we conclude that activation of the A3AR reduces the prostate cancer growth by suppressing miR-21 expression and up-regulating tumor suppressor proteins such as maspin, PDCD4 and TPM1. These data support the use of A3AR agonists as a viable therapeutic option against the advanced forms of prostate cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1940. doi:1538-7445.AM2012-1940

©2012 American Association for Cancer Research
2012