Search

Ca2+ is a second messenger which regulates many functions directly related with cancer such as proliferation, differentiation and apoptosis. The intracellular Ca2+ concentration ([Ca2+],) is finely regulated by several mechanisms, among them ionic channels, the endoplasmic reticulum Ca2+-ATPase (SERCA), the plasma membrane calcium pump (PMCA) and the mitochondrial Ca2+ transport. In cancer, the tumour cell proliferates without control since the capacity to recognize apoptotic signals has been lost. The apoptosis is regulated by changes in several proteins, as caspases and the Bcl-2 family members, among others. Additionally, the "reticulum stress", promoted by the accumulation and aggregation of unfolded proteins in the interior of the endoplasmic reticulum (ER), ussually leads to apoptosis. The "reticulum stress" can be induced by several agents, remarkably with thapsigargin, a selective inhibitor of the SERCA, which in turn induces a large increment in [Ca2+],, leading to apoptosis. As a consequence, currently, derivatives of thapsigargin are successfully been assayed as anti-neoplastic agents. Ca2+ is then transferred to the mitochondria, where it is known to constitute a main apoptotic signal. On the other hand, several sphingolipids, such as ceramide and sphingosine, and their phosphorylated derivatives ceramide-1-phosphate and sphingosine-1-phosphate, directly involved in the [Ca2+]1 regulation, are also recognized as signal messengers related with cancer processes. In this review we discuss new evidences on the effect of several sphingolipids in the intracellular Ca2+ homeostasis and its relationship with apoptosis and cancer.

The intracellular Ca2+ concentration in all eukaryotic cells so far studied is 4 orders of magnitude lower than in the extracellular milieu. In trypanosomatids, the intracellular concentration of this cation is around 50 nM, even lower than in higher eukaryotics. This differential concentration is maintained by diverse transport systems at the plasma membrane level and at certain intracellular organelles. In the case of trypanosomatids it have been identified the presence of an electrophoretic uniporter at the internal membrane of the unique giant mitochondrion of these parasites, showing identical kinetics properties to the homologous system of higher eukaryotics. Thus, the low Ca2+ affinity of this system is not compatible with its putative function of maintaining intracellular Ca2+ at the submicromolar level. Contrary to previous reports, we have identified a Ca(2+)-ATPase in the plasma membrane of Leishmania braziliensis, Leishmania mexicana, Trypanosoma cruzi and Trypanosoma brucei. The enzyme possesses a high Ca2+ affinity (Km Ca2+ = 0.5 microM), is Mg(2+)-dependent and activatable by calmodulin purified from these hemoflagellates. The Ca(2+)-ATPase is sensitive to vanadate (Ki = 1 microM), thus typifying it as a "P" type ion pump. Vesicles from the plasma membrane of these parasites are able to accumulate Ca2+ against a concentration gradient. The kinetic properties of both transport and ATPase are essentially the same, thus suggesting the same molecular entity. The above results strongly suggest that the Ca(2+)-ATPase is the mechanism responsible for the long-term fine-tuning of intracellular Ca2+ at the submicromolar lever in trypanosomatids.