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Prepublished online as a Blood First Edition Paper on December 19, 2002; DOI 10.1182/blood-2002-09-2730.
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Blood, 15 April 2003, Vol. 101, No. 8, pp. 3220-3228
NEOPLASIA
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 Giannì,
Luisa Diomede,
Laura M. Machesky,
Jocelyne Enouf, and
Béla Papp
From U348 Institut National de la Santé
et de la Recherche Médicale (INSERM), IFR Circulation
Lariboisière, Hôpital Lariboisière, Paris,
France; School of Biosciences, University of
Birmingham, United Kingdom; and Molecular Biochemistry and
Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Milano,
Italy.
Sarco-endoplasmic reticulum calcium ATPase
(SERCA) enzymes 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
pharmacologic 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 nicotinamide
adenine dinucleotide phosphate (NADPH) oxidase activity and
CD11b marker expression induced by suboptimal concentrations of ATRA
(50 nM) in both cell lines. Analysis of cellular calcium homeostasis 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 2 drugs. In addition, we found that retinoic acid
receptor  (RAR) and PML-RAR proteins are protected from
ATRA-induced proteolytic degradation by SERCA inhibition, indicating
that cellular calcium homeostasis 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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