Critical Review Endoplasmic reticulum calcium pumps and cancer Atousa Arbabian, 1 Jean-Philippe Brouland, 2 Pascal Ge´le´bart, 3 Tu¨nde Kova`cs, 4 Re´gis Bobe, 5 Jocelyne Enouf, 6 and Be´la Papp 1 * 1 Institut National de la Sante´ et de la Recherche Me´dicale, Inserm UMR-S 940, Institut Universitaire d’He´matologie, Universite´ Paris Diderot-Paris 7, 16, rue de la Grange aux Belles, 75010 Paris, France 2 Service d’Anatomie et Cytologie Pathologique, Hoˆpital Lariboisie`re, France APHP, Universite´ Paris Diderot-Paris 7. 1, rue Ambroise Pare´, 75010, Paris, France 3 Department of Laboratory Medicine and Pathology, Cross Cancer Institute and University of Alberta, 11560 University Avenue, Edmonton, Alberta, Canada 4 Membrane Biology Research Group, Semmelweis University, Hungarian Academy of Sciences, Dio´ szegi u. 64, H-1113 Budapest, Hungary 5 U770 Inserm, 80 rue du Ge´ne´ral Leclerc 94276, Le Kremlin-Biceˆtre, France 6 U689 INSERM Hoˆpital Lariboisie`re 1, rue Ambroise Pare´, 75010 Paris, France Abstract. Endoplasmic reticulum calcium homeostasis is involved in a multitude of signaling, as well as ‘‘house-keeping’’ functions that control cell growth, differentiation or apoptosis in every human/eukaryotic cell. Calcium is actively accumulated in the endoplasmic reticulum by Sarco/Endoplasmic Reticulum Calcium transport ATPases (SERCA enzymes). SERCA- dependent calcium transport is the only calcium uptake mechanism in this organelle, and therefore the regulation of SERCA function by the cell constitutes a key mechanism to adjust calcium homeostasis in the endoplasmic reticulum depending on the cell type and its state of differentiation. The direct pharmacological modulation of SERCA activity affects cell differentiation and survival. SERCA expression levels can undergo significant changes during cell differentiation or tumorigenesis, leading to modified endoplasmic reticulum calcium storage. In several cell types such as cells of hematopoietic origin or various epithelial cells, two SERCA genes (SERCA2 and SERCA3) are simultaneously expressed. Expression levels of SERCA3, a lower calcium affinity calcium pump are highly variable. In several cell systems SERCA3 expression is selectively induced during differentiation, whereas during tumorigenesis and blastic transformation SERCA3 expression is decreased. These observations point at the existence of a cross-talk, via the regulation of SERCA3 levels, between endoplasmic reticulum calcium homeostasis and the control of cell differentiation, and show that endoplasmic reticulum calcium homeostasis itself can undergo remodeling during differentiation. The investigation of the anomalies of endoplasmic reticulum differentiation in tumor and leukemia cells may be useful for a better understanding of the contribution of calcium signaling to the establishment of malignant phenotypes. VC 2011 International Union of Biochemistry and Molecular Biology, Inc. Volume 37, Number 3, May/June 2011, Pages 139–149  E-mail: bela.papp@inserm.fr (or) belapapp2@yahoo.fr Keywords: SERCA, endoplasmic reticulum, calcium, cancer, differentiation 1. Introduction Calcium is a ubiquitous second messenger involved in a mul- titude of cellular functions including secretion, motility, neu- ronal activity, cell proliferation, differentiation, or apoptosis [1]. Cellular calcium homeostasis and signaling are main- tained by a specialized set of proteins such as calcium chan- nels, calcium pumps, calcium/cation exchangers, calcium sensors, and calcium-activated effectors. Located in specific cellular compartments and membranes, these proteins function in concert to maintain intracellular calcium storage organelle structure, calcium concentration gradients, and fluxes in a resting cell, or during cell activation. This calcium homeostatic protein ‘‘toolkit" [2] functions in a highly *Address for correspondence: Be´la Papp, PhD, Inserm U940, Institut Universitaire d’He´matologie, Hoˆpital Saint-Louis, 16, rue de la Grange aux Belles, 75010 Paris, France. Tel.: þ33 6 86 08 83 09; fax number: þ33 1 53 72 40 13; E-mail: bela.papp@ inserm.fr (or) belapapp2@yahoo.fr. Received 8 November 2010; accepted 15 December 2010 DOI: 10.1002/biof.142 Published online 14 June 2011 in Wiley Online Library (wileyonlinelibrary.com) 139