Purinergic Receptor Expression and Cellular Responses to Purinergic Agonists in Human Prostate Cancer Cells

Abstract

Extracellular nucleotides were first proposed as signaling molecules in 1972 (1). Signaling through purinergic receptors is ubiquitous due to the diversity of purine and pyrimidine ligands, the number of receptors and extracellular nucleotidases. Purinergic signaling has been shown to play a role in many pathways including neurotransmission (2), cell differentiation, hormone secretion, vasodilation, cell proliferation, wound healing and apoptosis (3). There are two distinct families of purinergic receptors: P1 receptors for adenosine and P2 receptors for ATP/ADP and UTP/UDP ligands. P2 receptors are further divided into ligand-gated ion channel receptors, P2X, and G protein-coupled receptor, P2Y, subfamilies. To date, four P1 receptors (A 1,2a,2b,3 ), seven P2X receptors (P2X 1-7 ) and eight P2Y receptors (P2Y 1,2,4,6,11-14 ) have been identified in mammalian cells (4). The adenosine receptor subtypes A 1 and A 3 downregulate the production of cAMP, while A 2a and A 2b subtypes up-regulate the production of cAMP. Activation of P2X receptors leads to an influx of cations from the extracellular space, while activation of P2Y receptors leads to either an elevation of intracellular Ca 2+ from endoplasmic reticulum stores or down-regulation of cAMP production depending on the specific subtype of P2Y receptor activated.Growth suppression by the P2 agonist, ATP, was demonstrated first by Rapaport in 1983 (5). Exogenous ATP was shown to suppress the growth of pancreatic and colon cancer by causing cell-cycle arrest in S-phase. To date, the anticancer activity of extracellular nucleotides has been investigated in many types of cancer, including leukemia, melanoma and non-melanoma skin cancer, colorectal cancer, lung cancer, cervical cancer, prostate cancer (PCa) and squamous cell skin cancer (6). These led to clinical trials in patients with colorectal and non-small cell lung cancer that showed promising results with limited side-effects (7-9).PCa is the most frequently diagnosed cancer in North American men and the second leading cause of cancerrelated death in American men. It was estimated that there would be approximately 180,890 new cases of PCa and 26,5120 related deaths in the United States alone in 2016 (10). Current standard treatments for advanced PCa include various hormonal therapies whose goal is the ablation of androgens and their action (11). Even though 70% to 80% of patients respond well to first-line treatment, most patients eventually develop castrate-resistant disease (CRPCa) (12). Novel therapy therefore is needed to eliminate both early and 529 Τhis article is freely accessible online.

Extracellular Adenine Nucleotides and Adenosine Modulate the Growth and Survival of THP-1 Leukemia Cells

“…Adenosine has been found to both inhibit and stimulate the proliferation of cancer cells [26]. As in our study, an overwhelming number of publications describe its antiproliferative activity, including in prostate cancer [30], ovarian cancer [31], cholangiocarcinoma [32] and AML [28,29]. ATP and ADP (in the low micromolar range) are competitive inhibitors of 5 -nucleotidase that hydrolyze AMP to adenosine and inorganic phosphate.…”

Inhibitory Effects of ATP and Adenosine on Cholangiocarcinoma Cell Proliferation and Motility

“…Many studies have shown that a concentration of ATP of 100 μM or higher inhibited cancer cell proliferation; while a concentration of ATP lower than 10 μM may stimulate cancer cell proliferation. Our group has recently reported the growth inhibition induced byATP at 32 μM (log[ATP]=-4.5) and higher doses on prostate cancer cell lines (29). In addition, ATP at a very high dose in the range of milli molar was reported to induce cytotoxicity and apoptosis in many cancer types such as hepatoma, adenocarcinoma, and cervical cancer cells (24,(30)(31)(32)(33).…”

Purinergic Signalling: Therapeutic Developments

“…Prostate cancer cells are sensitive to extracellular ATP. ATP and adenosine inhibit the growth of human prostate cancer cells ( Lertsuwan et al, 2017 ), identified at that time to act via P2Y 1 , P2Y 2 and/or P2Y 4 , P2Y 6 and P2Y 11 R subtypes. Activation of P2Y 1 R inhibited growth and induced cell death of prostate cancer PC-3 cells and P2Y 1 R agonists were claimed to be therapeutically promising for prostate cancer ( Wei et al, 2011 ).…”