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 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.
Maaser
K
K
Medical Clinic I, Gastroenterology/Infectious Diseases/Rheumatology, Benjamin Franklin Clinics, Free University of Berlin, Hindenburgdamm 30, 12200 Berlin, Germany.
Höpfner
M
M
Kap
H
H
Sutter
A P
AP
Barthel
B
B
von Lampe
B
B
Zeitz
M
M
Scherübl
H
H
D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D017931:DNA Primers / Q000737:chemistry; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006801:Humans; D020287:In Situ Nick-End Labeling; D009711:Nucleotides / Q000494:pharmacology*; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058473:Receptors, Purinergic P2Y2; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012964:Sodium / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D017931:DNA Primers; D009711:Nucleotides; C546385:P2RY2 protein, human; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; D012964:Sodium; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D002118:Calcium