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Expression and Responsiveness of P2Y₂ Receptors in Human Endometrial Cancer Cell Lines

Endocrinology and Reproduction Research Branch (A.C.K., T.-A.K., M.T., S.S.S.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and Department of Obstetrics and Gynecology (A.S.-M., O.O.), University of Lubeck, D-23538 Lubeck, Germany

Address correspondence and requests for reprints to: Stanko Stojilkovic, Ph.D., Section on Cellular Signaling, Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, Building 49, Room 6A-36, 49 Convent Drive, Bethesda, Maryland 20892-4510. E-mail: stankos{at}helix.nih.gov

In single endometrial carcinoma HEC-1A and Ishikawa cells, ATP induced a rapid and extracellular Ca²⁺-independent rise in cytosolic Ca²⁺ concentration ([Ca²⁺]_i) in a dose-dependent manner, with an ED₅₀ of about 10 µM. The spike phase was followed by a sustained plateau phase that was dependent on Ca²⁺ influx through voltage-insensitive Ca²⁺ channels, whose gating was controlled by a capacitative Ca²⁺ entry mechanism. ADP was less potent in raising the cystolic Ca²⁺ concentration, and AMP and adenosine were ineffective. The order of agonist potency for this receptor was ATP = UTP > ATP--S>>ADP. Several other agonists, including ß,-methylene-ATP, 2-MeS-ATP, and BzATP were ineffective. This ligand-selective profile indicates the expression of the P2Y₂R subtype in endometrial cells. Accordingly, reverse transcription-PCR using P2Y₂ primers amplified the expected transcript from both cell lines. The coupling of these receptors to phospholipase C was confirmed by the ability of ATP to increase inositol 1,4,5-trisphosphate and diacylglycerol productions. These receptors are also coupled to the phospholipase D-1 pathway, leading to accumulation of phosphatidic acid. Activation of P2Y₂ receptors by a slowly degradable ATP analog, ATP--S, was associated with a significant suppression of cell proliferation without affecting the cellular apoptosis. These results indicate that P2Y₂ receptors may participate in control of the cell cycle of endometrial carcinoma cells.

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