Extracellular nucleotides inhibit growth of human oesophageal cancer cells via P2Y(2)-receptors

Extracellular ATP is known to inhibit growth of various tumours by activating specific purinergic receptors (P2-receptors). Since the therapy of advanced oesophageal cancer is unsatisfying, new therapeutic approaches are mandatory. Here, we investigated the functional expression and potential antiproliferative effects of P2-purinergic receptors in human oesophageal cancer cells. Prolonged incubation of primary cell cultures of human oesophageal cancers as well as of the squamous oesophageal cancer cell line Kyse-140 with ATP or its stable analogue ATPγS dose-dependently inhibited cell proliferation. This was due to both an induction of apoptosis and cell cycle arrest. The expression of P2-receptors was examined by RT-PCR, immunocytochemistry, and [Ca(2+)](i)-imaging. Application of various extracellular nucleotides dose-dependently increased [Ca(2+)](i). The rank order of potency was ATP=UTP>ATPγS>ADP=UDP. 2-methylthio-ATP and α,β-methylene-ATP had no effects on [Ca(2+)](i). Complete cross-desensitization between ATP and UTP was observed. Moreover, the phospholipase C inhibitor U73122 dose-dependently reduced the ATP triggered [Ca(2+)](i) signal. The pharmacological features strongly suggest the functional expression of G-protein coupled P2Y(2)-receptors in oesophageal squamous cancer cells. P2Y(2)-receptors are involved in the antiproliferative actions of extracellular nucleotides. Thus, P2Y(2)-receptors are promising target proteins for innovative approaches in oesophageal cancer therapy. British Journal of Cancer (2002) 86, 636–644. DOI: 10.1038/sj/bjc/6600100 www.bjcancer.com © 2002 Cancer Research UK