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Prepublished online as a Blood First Edition Paper on December 19, 2002; DOI 10.1182/blood-2002-09-2730.
Submitted September 9, 2002
Accepted December 10, 2002
Enhancement of ATRA-induced cell differentiation by inhibition of calcium accumulation into the endoplasmic reticulum. cross-talk between RAR and calcium-dependent signaling
Sophie Launay*, Maurizio Gianni, Luisa Diomede, Laura M Machesky, Jocelyne Enouf, and Bela Papp
Hopital Lariboisiere, Unite 348, INSERM, Paris, France
School of Biosciences, University of Birmingham, Birmingham, United Kingdom
Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy
* Corresponding author; email: s.launay{at}bham.ac.uk.
Sarco-Endoplasmic Reticulum Calcium ATPase enzymes (SERCA) control calcium-induced cellular activation by accumulating calcium from the cytosol into the endoplasmic reticulum (ER). To better understand the role of SERCA proteins and cellular calcium homeostasis in all-trans retinoic acid (ATRA)-induced differentiation, we investigated the effect of pharmacological inhibition of SERCA-dependent calcium uptake into the ER on ATRA-induced differentiation of the HL-60 myelogenous and the NB4 promyelocytic cell lines. SERCA inhibitors di-tert-butyl-benzohydroquinone (tBHQ), thapsigargin and cyclopiazonic acid significantly enhanced the induction of NADPH oxidase activity and CD11b marker expression induced by suboptimal concentrations of ATRA (50 nM) in both cell lines. Analysis of cellular calcium homeostasis by fluorimetry revealed that a 60% mobilization of the total SERCA-dependent intracellular calcium pool was necessary to obtain enhancement of ATRA-dependent differentiation by tBHQ. Moreover, after 3 days of ATRA treatment in combination with tBHQ, NB4 cells showed a significantly decreased calcium mobilization compared with treatments with tBHQ or ATRA alone, suggesting that enhanced differentiation and calcium mobilization are causally related. Interestingly, several ATRA-resistant NB4-derived cell lines were partially responsive to the differentiation-inducing effect of the combination of the two drugs. In addition, we found that RAR and PML-RAR proteins are protected from ATRA-induced proteolytic degradation by SERCA inhibition, indicating that cellular calcium homeostasis, and particularly SERCA-dependent calcium pools may interact with signaling systems involved in the control of ATRA-dependent transcriptional activity. By linking calcium to ATRA-dependent signaling, our data open new avenues in the understanding of the mechanisms of differentiation-induction therapy of leukemia.
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