IMPAIRMENT OF ATP-INDUCED CA2-SIGNALING IN HUMAN THYROID-CANCER CELLS()

Extracellular nucleotides like ATP that activate the Ca2+-phosphatidyl inositol (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 Ca2+ signalling is altered by malignant tra nsformation Extracellular ATP caused a biphasic increase in cytosolic free Ca2+ ([Ca2+](i)) in normal human thyrocytes and in human follicul ar (FTC) and papillary (PTC) thyroid carcinoma cells. In FTC and PTC c ell lines the dose-response curves for ATP-induced changes in [Ca2+](i ) were shifted to the right when compared with normal thyrocytes, wher eas in undifferentiated thyroid carcinoma (UTC) cells even high concen trations of ATP (500 mu M) failed to stimulate a rise in [Ca2+](i). By contrast, ATP stimulated inositol 1,4,5-trisphosphate (IP3) formation and capacitative Ca2+ entry was operational as judged by thapsigargin in normal thyrocytes and all thyroid cancer cells. Thus, P-2y-puriner gic receptors are expressed on thyroid tumor cells independent of degr ee of differentiation. In UTC cells, however, impairment in the Ca2+-p hosphatidylinositol (PI) signalling cascade occurs distal to the forma tion of IF, and proximal to the activation of capacitative Ca2+ entry. Disturbed ATP-induced Ca2+-signalling and alterations in the Ca2+-PI signalling cascade may contribute to decreased expression or loss of s pecific thyroid functions in thyroid cancer cells. (C) 1997 Elsevier S cience Ireland Ltd.