Cell proliferation depends on mitochondrial Ca2+ uptake: inhibition by salicylate.
Store-operated Ca2+ entry (SOCE) is a ubiquitous Ca2+ influx pathway involved in control of multiple cellular and physiological processes including cell proliferation. Recent evidence has shown that SOCE depends critically on mitochondrial sinking of entering Ca2+ to avoid Ca2+-dependent inactivation. Thus, a role of mitochondria in control of cell proliferation could be anticipated. We show here that activation of SOCE induces cytosolic high [Ca2+] domains that are large enough to be sensed and avidly taken up by a pool of nearby mitochondria. Prevention of mitochondrial clearance 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 metabolite of aspirin, depolarize partially mitochondria and inhibit mitochondrial Ca2+ uptake, as revealed by mitochondrial Ca2+ measurements with targeted aequorins. This salicylate-induced inhibition of mitochondrial Ca2+ sinking prevented SOCE and impaired cell growth of Jurkat and human colon cancer cells. Finally, direct blockade of SOCE by the pyrazole derivative BTP-2 was sufficient to arrest cell growth. Taken together, our 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 explaining the reported anti-proliferative and anti-tumoral actions of aspirin and dietary salicylates.
Núñez
Lucía
L
Instituto de Biología y Genética Molecular (IBGM), c/Sanz y Forés s/n. 47003-Valladolid, Spain.
Valero
Ruth A
RA
Senovilla
Laura
L
Sanz-Blasco
Sara
S
García-Sancho
Javier
J
Villalobos
Carlos
C
D000813:Anilides / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003600:Cytosol / Q000737:chemistry; D019073:HT29 Cells; D006801:Humans; D019169:Jurkat Cells; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D012459:Salicylates / Q000494:pharmacology*; D013830:Thiadiazoles / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
C476308:4-methyl-4'-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-1,2,3-thiadiazole-5-carboxanilide; D000813:Anilides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D012459:Salicylates; D013830:Thiadiazoles; D002118:Calcium