A supramicromolar elevation of intracellular free calcium ([Ca2+](i)) is consistently required to induce the execution phase of apoptosis
(2002) Cell Death & Differentiation — Vol. 9, n° 5, p. 561-573 (2002)
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- Many agents, such as the endoplasmic reticulum Ca2+ ATPase inhibitor, thapsigargin, or the ionophore, ionomycin, induce apoptosis by transiently elevating [Ca2+](i). The role of [Ca2+](i) in apoptosis induced by agents that do not immediately increase [Ca2+](i), such as 5-FdUr, TGFbeta-1, doxorubicin, or radiation, is far more controversial. In the present paper, [Ca2+](i) was measured continuously for 120 h, in prostate and bladder cancer cell lines exposed to these four agents: 5-FdUR, TGFbeta-1, doxorubicin, or radiation. Each of them consistently induced a delayed [Ca2+](i) rise associated with the morphological changes that characterize the execution phase of apoptosis (i.e. rounding, blebbing). This [Ca2+](i) rise occurred in two consecutive steps (less than or equal to 10 muM and > 10 muM) and resulted from a Ca2+ influx from the extracellular medium. This delayed supramicromolar [Ca2+](i) rise was also observed previously in breast, prostate and bladder cancer cell lines exposed to thapsigargin. This influx regulated transcriptional reprogramming of Gadd153 and is required to activate cytochrome c release, caspase-3 activation, loss of clonal survival and DNA fragmentation. When cells were maintained in low extracellular Ca2+ media, these phenomena were temporarily delayed but occurred on return to normal Ca2+ medium. Similarly, apoptosis could be delayed by overexpressing the Ca2+-binding proteins, Calbindin-D-28K and parvalbumin. As this delayed greater than or equal to 10 muM [Ca2+](i) elevation was observed in a number of cell lines exposed to a variety of different agents, we conclude that such elevation constitutes a key and general event of apoptosis in these malignant cells.
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Tombal, B., Denmeade, S., Gillis, J.-M., & Isaacs, J. (2002). A supramicromolar elevation of intracellular free calcium ([Ca2+](i)) is consistently required to induce the execution phase of apoptosis. Cell Death & Differentiation, 9(5), 561-573. https://doi.org/10.1038/sj.cdd.4400999 (Original work published 2002)