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

• Published in: British journal of cancer 2002-02, Vol.86 (4), p.636-644
• Main Authors: Maaser, K, Höpfner, M, Kap, H, Sutter, A P, Barthel, B, von Lampe, B, Zeitz, M, Scherübl, H
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Calcium - metabolism; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Caspase 3; Caspases - metabolism; Cell Cycle - drug effects; Cell Division - drug effects; DNA Primers - chemistry; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Fluorescent Antibody Technique; Humans; In Situ Nick-End Labeling; Nucleotides - pharmacology; Receptors, Purinergic P2 - metabolism; Receptors, Purinergic P2Y2; Reverse Transcriptase Polymerase Chain Reaction; Sodium - metabolism; Tumor Cells, Cultured - drug effects
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6600100

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 ATP gamma S 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>ATP gamma S>ADP=UDP. 2-methylthio-ATP and alpha,beta-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.