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Impairment of ATP-induced Ca2+ -signalling in human thyroid cancer cells
1Abteilung Klinische Endokrinologie, Medizinische Hochschule Hannover, Germany.
Abstract:
Extracellular nucleotides like ATP that activate the Ca2+ -phosphatidylinositol (PI) signalling pathway have been suggested to participate in the regulation of normal human thyroid function. We examined, whether P2y-purinergic receptors are expressed on human thyroid cancer cells and whether post-receptor Ca2+ signalling is altered by malignant transformation. Extracellular ATP caused a biphasic increase in cytosolic free Ca2+ ([Ca2+]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 [Ca2+]i were shifted to the right when compared with normal thyrocytes, whereas in undifferentiated thyroid carcinoma (UTC) cells even high concentrations of ATP (500 microM) 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, P2y-purinergic receptors are expressed on thyroid tumor cells independent of degree of differentiation. In UTC cells, however, impairment in the Ca2+ -phosphatidylinositol (PI) signalling cascade occurs distal to the formation of IP3 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 specific thyroid functions in thyroid cancer cells.
Insights
Extracellular ATP activates calcium-phosphatidylinositol (PI) signaling in thyroid cells. While P2y receptors are present in thyroid tumors, signaling is impaired in undifferentiated cancers, potentially affecting thyroid function.
Area of Science:
- Endocrinology
- Molecular Biology
- Cancer Research
Background:
- Extracellular nucleotides, such as adenosine triphosphate (ATP), play a role in regulating normal human thyroid function via the calcium-phosphatidylinositol (PI) signaling pathway.
- The expression and function of P2y-purinergic receptors and their downstream signaling in human thyroid cancer remain incompletely understood.
Purpose of the Study:
- To investigate the expression of P2y-purinergic receptors on human thyroid cancer cells.
- To determine if post-receptor calcium (Ca2+) signaling is altered during malignant transformation of thyroid cells.
- To elucidate the specific defects in the Ca2+-PI signaling cascade in different types of thyroid tumors.
Main Methods:
- Measurement of cytosolic free Ca2+ ([Ca2+]i) concentration in response to extracellular ATP stimulation.
- Analysis of inositol 1,4,5-trisphosphate (IP3) formation.
- Assessment of capacitative Ca2+ entry using thapsigargin in normal thyrocytes and various thyroid cancer cell lines (follicular, papillary, and undifferentiated).
Main Results:
- Extracellular ATP induced a biphasic increase in [Ca2+]i in normal thyrocytes and differentiated thyroid carcinoma cells (follicular and papillary).
- Dose-response curves for ATP-induced [Ca2+]i changes were shifted rightward in follicular and papillary cells compared to normal thyrocytes.
- In undifferentiated thyroid carcinoma cells, high ATP concentrations failed to stimulate [Ca2+]i rise, despite intact IP3 formation and capacitative Ca2+ entry.
- P2y-purinergic receptors were expressed on all tested thyroid tumor cells, irrespective of differentiation status.
Conclusions:
- P2y-purinergic receptors are expressed on human thyroid tumor cells, regardless of their differentiation.
- In undifferentiated thyroid carcinoma cells, a defect in the Ca2+-PI signaling cascade occurs downstream of IP3 formation and upstream of capacitative Ca2+ entry.
- Altered ATP-induced Ca2+ signaling and disruptions in the Ca2+-PI pathway may contribute to the reduced expression or loss of specific thyroid functions in thyroid cancer cells.