Impairment of ATP-induced Ca 2+-signalling in human thyroid cancer cells

Abstract

Extracellular nucleotides like ATP that activate the Ca 2+-phosphatidylinositol (PI) signalling pathway have been suggested to participate in the regulation of normal human thyroid function. We examined, whether P 2y-purinergic receptors are expressed on human thyroid cancer cells and whether post-receptor Ca 2+ signalling is altered by malignant transformation. Extracellular ATP caused a biphasic increase in cytosolic free Ca 2+ ([Ca 2+] i) in normal human thyrocytes and in human follicular (FTC) and papillary (PTC) thyroid carcinoma cells. In FTC and PTC cell lines the dose-response curves for ATP-induced changes in [Ca 2+] i were shifted to the right when compared with normal thyrocytes, whereas in undifferentiated thyroid carcinoma (UTC) cells even high concentrations of ATP (500 μM) failed to stimulate a rise in [Ca 2+] i. By contrast, ATP stimulated inositol 1,4,5-trisphosphate (IP 3) formation and capacitative Ca 2+ entry was operational as judged by thapsigargin in normal thyrocytes and all thyroid cancer cells. Thus, P 2y-purinergic receptors are expressed on thyroid tumor cells independent of degree of differentiation. In UTC cells, however, impairment in the Ca 2+-phosphatidylinositol (PI) signalling cascade occurs distal to the formation of IP 3 and proximal to the activation of capacitative Ca 2+ entry. Disturbed ATP-induced Ca 2+-signalling and alterations in the Ca 2+-PI signalling cascade may contribute to decreased expression or loss of specific thyroid functions in thyroid cancer cells.