HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 571/1/57    most recent jphysiol.2005.100586v2 jphysiol.2005.100586v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Núñez, L. Articles by Villalobos, C. Search for Related Content PubMed PubMed Citation Articles by Núñez, L. Articles by Villalobos, C. Related Collections Cellular

¹ Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid and CSIC, C/Sanz y Forés s/n. 47003-Valladolid, Spain

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.

(Received 24 October 2005; accepted after revision 7 December 2005; first published online 8 December 2005)
Corresponding author C. Villalobos: Instituto de Biología y Genética Molecular (IBGM), c/Sanz y Forés s/n. 47003-Valladolid, Spain. Email: carlosv{at}ibgm.uva.es

This article has been cited by other articles:

				J. Roman, A. F. de Arriba, S. Barron, P. Michelena, M. Giral, M. Merlos, E. Bailon, M. Comalada, J. Galvez, A. Zarzuelo, et al. UR-1505, a New Salicylate, Blocks T Cell Activation through Nuclear Factor of Activated T Cells Mol. Pharmacol., August 1, 2007; 72(2): 269 - 279. [Abstract] [Full Text] [PDF]