QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online November 23, 2005
doi: 10.1242/10.1242/jcs.02663

This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted 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 Mignen, O. Articles by Capiod, T. Search for Related Content PubMed PubMed Citation Articles by Mignen, O. Articles by Capiod, T.

Carboxyamidotriazole-induced inhibition of mitochondrial calcium import blocks capacitative calcium entry and cell proliferation in HEK-293 cells

¹ Department of Pharmacology and Physiology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA
² Department of Neuroscience, Medical College of Ohio, 3036 Arlington Avenue, Toledo, OH 43614, USA
³ INSERM, EMI 0228, IFR118, Université des Sciences et Technologies de Lille 1, Bât. SN3, 59655 Villeneuve d'Ascq CEDEX, France
⁴ INSERM, U442, IFR46, Université Paris-Sud, Bât.443, 91405 Orsay CEDEX, France

^* Author for correspondence (e-mail: thierry.capiod{at}univ-lille1.fr)

Accepted 25 August 2005

Blocking calcium entry may prevent normal and pathological cell proliferation. There is evidence suggesting that molecules such as carboxyamidotriazole, widely used in anti-cancer therapy based on its ability to block calcium entry in nonexcitable cells, also have antiproliferative properties. We found that carboxyamidotriazole and the capacitative calcium entry blocker 2-aminoethoxydiphenyl borate inhibited proliferation in HEK-293 cells with IC₅₀ values of 1.6 and 50 µM, respectively. Capacitative calcium entry is activated as a result of intracellular calcium store depletion. However, non-capacitative calcium entry pathways exist that are independent of store depletion and are activated by arachidonic acid and diacylglycerol, generated subsequent to G protein coupled receptor stimulation. We found that carboxyamidotriazole completely inhibited the capacitative calcium entry and had no effect on the amplitude of arachidonic-acid-activated non-capacitative calcium entry. However, investigation of the effects of carboxyamidotriazole on mitochondrial calcium dynamics induced by carbachol, capacitative calcium entry and exogenously set calcium loads in intact and digitonin-permeabilized cells revealed that carboxyamidotriazole inhibited both calcium entry and mitochondrial calcium uptake in a time-dependent manner. Mitochondrial inner-membrane potential was altered by carboxyamidotriazole treatment, suggesting that carboxyamidotriazole antagonizes mitochondrial calcium import and thus local calcium clearance, which is crucial for the maintenance of capacitative calcium entry.

Key words: CAI, 2-APB, CCE, Mitochondrial respiration, ARC

This article has been cited by other articles:

				A. F. Pla, C. Grange, S. Antoniotti, C. Tomatis, A. Merlino, B. Bussolati, and L. Munaron Arachidonic Acid-Induced Ca2+ Entry Is Involved in Early Steps of Tumor Angiogenesis Mol. Cancer Res., April 1, 2008; 6(4): 535 - 545. [Abstract] [Full Text] [PDF]

				L. Lipskaia, C. Pinet, Y. Fromes, S. Hatem, I. Cantaloube, A. Coulombe, and A.-M. Lompre Mutation of {delta}-Sarcoglycan Is Associated with Ca2+-Dependent Vascular Remodeling in the Syrian Hamster Am. J. Pathol., July 1, 2007; 171(1): 162 - 171. [Abstract] [Full Text] [PDF]