1. Calcium signaling and Cancer Chemoprevention.

Mitochondria shapes cytosolic Ca²⁺ signals and is essential for control of store-operated Ca²⁺ entry, a Ca²⁺ influx pathway involved in cell proliferation. Accordingly, an important role of mitochondria in control of proliferation is anticipated. In addition, mitochondria has been proposed as target for cancer chemoprevention. Thus, we are investigating the role of mitochondria in cell proliferation and the possibility that mitochondria may be the target of non-steroidal anti-imflammatory drugs (NSAIDs), particularly ASPIRIN that inhibit tumour cell growth and protect against a number of cancers.

Specifically, we have shown that activation of SOCE induces cytosolic high [Ca²⁺] domains that are large enough to be sensed and cleared by a pool of nearby mitochondria. These mitochondria take up large amounts of Ca²⁺ that provoke increases of mitochondrial [Ca²⁺] to near the mM range. Prevention of mitochondrial sinking of the entering Ca²⁺ inhibited both SOCE and cell proliferation in several cell types including Jurkat and human colon cancer cells. In addition, we find that therapeutic concentrations of salicylate, the major aspirin metabolite, depolarise partially mitochondria and inhibit mitochondrial Ca²⁺ uptake, as revealed by mitochondrial Ca²⁺ measurements with targeted, low affinity aequorin. The salicylate-induced inhibition of mitochondrial Ca²⁺ sinking prevents SOCE and impairs cell growth of Jurkat and human colon cancer cells. Finally, the direct blockade of SOCE by the pyrazole derivative BTP2 was sufficient to arrest cell growth. These results reveal that cell proliferation depends critically on mitochondrial Ca²⁺ uptake and suggest that inhibition of tumour cell proliferation by salicylate may be due to interference with mitochondrial Ca²⁺ uptake, which is essential for sustaining SOCE. This novel mechanism may contribute to explain the reported anti-proliferative and anti-tumoral properties of aspirin and dietary salicylates.

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