Purinergic Signal. 2013 Jun;9(2):271-80. doi: 10.1007/s11302-012-9350-3.

A2B adenosine receptor blockade inhibits growth of prostate cancer cells.

Wei Q, Costanzi S, Balasubramanian R, Gao ZG, Jacobson KA.

Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0810, USA.

 

Abstract

The role of the A2B adenosine receptor (AR) in prostate cell death and growth was studied. The A2B AR gene expression quantified by real-time quantitative RT-PCR and Western blot analysis was the highest among four AR subtypes (A1, A2A, A2B, and A3) in all three commonly used prostate cancer cell lines, PC-3, DU145, and LNCaP. We explored the function of the A2B AR using PC-3 cells as a model. The A2B AR was visualized in PC-3 cells by laser confocal microscopy. The nonselective A2B AR agonist NECA and the selective A2B AR agonist BAY60-6583, but not the A2A AR agonist CGS21680, concentration-dependently induced adenosine 3′,5′-cyclic monophosphate (cyclic AMP) accumulation. NECA diminished lactate dehydrogenase (LDH) release, TNF-α-induced increase of caspase-3 activity, and cycloheximide (CHX)-induced morphological changes typical of apoptosis in PC-3 cells, which were blocked by a selective A2B AR antagonist PSB603. NECA-induced proliferation of PC-3 cells was diminished by siRNA specific for the A2B AR. The selective A2B AR antagonist PSB603 was shown to inhibit cell growth in all three cell lines. Thus, A2B AR blockade inhibits growth of prostate cancer cells, suggesting selective A2B AR antagonists as potential novel therapeutics.

PMID: 23315335

 

Supplement: 

Prostate cancer is one of the most frequently diagnosed cancers in man, but the means of treatment of this disease is still limited. G protein-coupled receptors (GPCRs) are emerging targets for cancer. It has been reported that the A2B adenosine receptor (AR) is one of those most abundantly expressed in the human prostate cancer cells. However, the role of the A2B AR in prostate cancer has not previously been well explored, although it has been studied in several other types of tumors.

In the present study, we found that the expression level of the A2B AR was the highest among the four AR subtypes in all three commonly used prostate cancer cell lines. We subsequently studied the A2B AR signaling in regulating cell death and growth using PC-3 cells as a model. We further examined the role of the A2B AR in proliferation of the three most commonly used cell lines, PC-3 (androgen-independent), DU145 (androgen-independent), and LNCaP (androgen-dependent), using a selective A2B AR antagonist PSB603. We found that A2B AR activation promoted cell growth. Both the A2B AR antagonist PSB603 and siRNA specific for the A2B AR slowed cell growth, suggesting that selective A2B AR blockade could be useful for the treatment of prostate cancer.

Administration of the naturally occurring AR antagonists, i.e. caffeine and theophylline, has long been suspected to counteract the growth of cancer. Both caffeine and theophylline are weak and non-selective A2B antagonists, which might have a role in both cancer promotion and prevention depending specific situations involved. In this study, a more potent and selective A2B AR antagonist PSB603 has been clearly shown to inhibit the growth of prostate cancer cells. It remains to be seen how general is the anti-proliferative effect of A2B AR antagonists in primary prostate cancer cells and other types of cancer cells.

The findings from the present study that the A2A AR is also relatively highly expressed in DU145 and LNCap cells, suggest that under some specific conditions, selective antagonists of the A2A AR may also have therapeutic role in prostate cancer management.

In addition to the high expression level of the A2B AR and P2Y1 receptors, which are activated by endogenous adenine nucleotides, and ectonucleotidases CD39 and CD73, which together degrade adenine nucleotides to produce adenosine, are also abundantly expressed in prostate cancer cells. It has been suggested that inhibition of either enzyme may find utility in cancer management. The present study demonstrated that A2B AR activation may have tumor-promoting effects, thus indicating that the tumorigenic effects of ectonucleotidases might be, at least in part, via the activation of the A2B AR, due to their ability to cleave ATP to produce adenosine. In summary, the present study demonstrated that activation of the A2B AR promotes and blockade of the A2B AR inhibits the growth of prostate cancer cells. Thus, A2B AR blockade might be a novel therapy for prostate cancer patients.graphic for A2B receptor prostate cancerAcknowledgements: This study was supported by the NIDDK Intramural Research Program, National Institutes of Health, Bethesda, MD, USA, the National Natural Science Foundation of China (No: 30940072), Guangdong Province Science and Technology Program (2012B031800263) and Nanfang Hospital, Southern Medical University, Guangzhou, China.

Contact:  Kenneth A. Jacobson, Ph.D., National Institute of Diabetes & Digestive & Kidney Diseases,

National Institutes of Health, Bldg. 8A, Rm. B1A-19, Bethesda, MD 20892-0810  USA, email:  kennethj@helix.nih.gov

 

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