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Originally published In Press as doi:10.1074/jbc.M201747200 on May 1, 2002

J. Biol. Chem., Vol. 277, Issue 29, 26310-26320, July 19, 2002
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Expression of Endomembrane Calcium Pumps in Colon and Gastric Cancer Cells
INDUCTION OF SERCA3 EXPRESSION DURING DIFFERENTIATION*

Pascal GélébartDagger §, Tünde Kovács||, Jean-Philippe Brouland**, Roosje van GorpDagger , Johannes GrossmannDagger Dagger , Nathalie Rivard§§, Yves Panis¶¶, Virginie MartinDagger , Raymonde BredouxDagger , Jocelyne EnoufDagger , and Béla PappDagger ||||

From the Dagger  Unité 348 INSERM, IFR-6, Hôpital Lariboisière, 75010 Paris, France,  National Institute of Haematology and Immunology, Daròczi ùt 24, 1113 Budapest, Hungary, ** Service d'Anatomie Pathologique, Hôpital Lariboisière, 75010 Paris, France, Dagger Dagger   Klinik und Poliklinik für Innere Medizin I, Klinikum der Universität Regensburg, 93042 Regensburg, Germany, §§ Faculté de Médecine, Université de Sherbrooke, 3001, 12e Avenue Nord, Sherbrooke, Québec J1H 5N4, Canada, and ¶¶ Service de Chirurgie Générale et Digestive, Hôpital Lariboisière, 75010 Paris, France

Calcium mobilization from the endoplasmic reticulum (ER) into the cytosol is a key component of several signaling networks controlling tumor cell growth, differentiation, or apoptosis. Sarco/endoplasmic reticulum calcium transport ATPases (SERCA-type calcium pumps), enzymes that accumulate calcium in the ER, play an important role in these phenomena. We report that SERCA3 expression is significantly reduced or lost in colon carcinomas when compared with normal colonic epithelial cells, which express this enzyme at a high level. To study the involvement of SERCA enzymes in differentiation, in this work differentiation of colon and gastric cancer cell lines was initiated, and the change in the expression of SERCA isoenzymes as well as intracellular calcium levels were investigated. Treatment of the tumor cells with butyrate or other established differentiation inducing agents resulted in a marked and specific induction of the expression of SERCA3, whereas the expression of the ubiquitous SERCA2 enzymes did not change significantly or was reduced. A similar marked increase in SERCA3 expression was found during spontaneous differentiation of post-confluent Caco-2 cells, and this closely correlated with the induction of other known markers of differentiation. Analysis of the expression of the SERCA3 alternative splice isoforms revealed induction of all three known iso-SERCA3 variants (3a, 3b, and 3c). Butyrate treatment of the KATO-III gastric cancer cells led to higher resting cytosolic calcium concentrations and, in accordance with the lower calcium affinity of SERCA3, to diminished ER calcium content. These data taken together indicate a defect in SERCA3 expression in colon cancers as compared with normal colonic epithelium, show that the calcium homeostasis of the endoplasmic reticulum may be remodeled during cellular differentiation, and indicate that SERCA3 constitutes an interesting new differentiation marker that may prove useful for the analysis of the phenotype of gastrointestinal adenocarcinomas.


* This work was supported in part by INSERM, by the Association pour la Recherche sur le Cancer, France, by Nestlé, France, by Research Grant T 032766 from OTKA, Hungary, and by APRIFEL, France.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

We dedicate our work to the memory of all victims of the tragedy of September 11, 2001.

§ Recipient of a doctoral fellowship from Nestlé, France, and from APRIFEL.

|| Recipient of the Bolyai János Research Fellowship of the Hungarian Academy of Sciences.

|||| To whom correspondence should be addressed: U. 348 INSERM, Hôpital Lariboisière, 8 Rue Guy Patin, 75010 Paris, France. Fax: 33-1- 49-95-85-79; E-mail: bela.papp@inserm.lrb.ap-hop-paris.fr.


Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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