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Cell proliferation depends on mitochondrial Ca2+ uptake: inhibition by salicylate

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dc.creator Núñez, Lucía
dc.creator Valero, Ruth A.
dc.creator Senovilla, Laura
dc.creator Sanz-Blasco, Sara
dc.creator García-Sancho, Javier
dc.creator Villalobos, Carlos
dc.date 2008-06-20T08:02:45Z
dc.date 2008-06-20T08:02:45Z
dc.date 2006-02-15
dc.date.accessioned 2017-01-31T01:44:30Z
dc.date.available 2017-01-31T01:44:30Z
dc.identifier Journal of Physiology 571(1): 57–73 (2006)
dc.identifier 0022-3751
dc.identifier http://hdl.handle.net/10261/5201
dc.identifier 10.1113/jphysiol.2005.100586
dc.identifier.uri http://dspace.mediu.edu.my:8181/xmlui/handle/10261/5201
dc.description 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.
dc.description We acknowledge grants VA04/02, VA115/02, VA071/02 and VA05/04 from Junta de Castilla y León, BFI2001-2073 and BFU2004-02764 from Spain's Ministerio de Educación y Ciencia (MEC) and FIS 03/1231, FIS 04/1510 from Instituto de Salud Carlos III. L.S. holds a FPI predoctoral fellowship from MEC. L.N. is supported by the ‘Ramón y Cajal’ Program from MEC.
dc.description Peer reviewed
dc.format 22195 bytes
dc.format application/pdf
dc.language eng
dc.publisher Wiley-Blackwell
dc.rights closedAccess
dc.title Cell proliferation depends on mitochondrial Ca2+ uptake: inhibition by salicylate
dc.type Artículo

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