Potentiality and Limitations of a Strategy for the Control of Cell Proliferation: The Block of Ca2+ Entry

Ca2+ signalling is involved in virtually all cellular processes: among the others, it controls cell survival, proliferation and death regulating a plethora of intracellular enzymes located in the cytoplasm, nucleus and organelles.

Changes in the cytosolic free Ca2+ concentration may be due either to release from the intracellular Ca2+ stores or to influx from the extracellular medium, through the opening of plasmamembrane calcium-permeable channels. In particular, Ca2+ entry from the extracellular space is a mechanism able to sustain long lasting intracellular Ca2+ elevations: this signal, activated by many growth factors and mitogens in normal and tumoral tissues, is linked to DNA transcription and duplication, finally leading to cell proliferation.

In the last years many informations have been provided about the transduction mechanisms related to Ca2+ entry induced by mitogenic factors, mostly binding to tyrosine kinase receptors, but also to G-protein coupled ones. Nevertheless, some key points remain to be fully clarified: among them, the molecular structure of the Ca2+ channels involved, their regulation by intracellular messengers, and the modes through which specificity is achieved.

The increasing knowledge on Ca2+ entry-dependent control of proliferation may provide a more satisfactory understanding of pathological alterations, including cancer progression and angiogenesis. A detailed description of the mechanisms that trigger Ca2+ entry, and in particular the definition of calcium-permeable channels and their modulators at the molecular levels, will greatly improve our possibility to take advantage of Ca2+ entry regulation as a therapeutic approach for the control of cell proliferation, designing antibodies or molecules with low side effects and specific channel blocker functions. The review will focuse on this topic.