Autonomous Rexinoid Death Signaling Is Suppressed by Converging Signaling Pathways in Immature Leukemia Cells

• Published in: Molecular endocrinology (Baltimore, Md.) Vol. 15; no. 7; pp. 1154 - 1169
• Main Authors: Benoit, G. R, Flexor, M, Besançon, F, Altucci, L, Rossin, A, Hillion, J, Balajthy, Z, Legres, L, Ségal-Bendirdjian, E, Gronemeyer, H, Lanotte, M
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01-07-2001
• Subjects: Apoptosis - drug effects; Blood; Cell Differentiation - drug effects; Cell Line; Cellular Biology; Culture Media; Cyclic AMP-Dependent Protein Kinases - metabolism; Dimerization; DNA Fragmentation; Drug Resistance; In Situ Nick-End Labeling; Leukemia, Promyelocytic, Acute - pathology; Life Sciences; NF-kappa B - metabolism; Receptors, Retinoic Acid - antagonists & inhibitors; Receptors, Retinoic Acid - metabolism; Retinoid X Receptors; Retinoids - metabolism; Retinoids - pharmacology; Signal Transduction; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism; Tumor Cells, Cultured
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/mend.15.7.0654

On their own, retinoid X receptor (RXR)-selective
ligands (rexinoids) are silent in retinoic acid receptor (RAR)-RXR
heterodimers, and no selective rexinoid program has been described as
yet in cellular systems. We report here on the rexinoid signaling
capacity that triggers apoptosis of immature promyelocytic NB4 cells as
a default pathway in the absence of survival factors. Rexinoid-induced
apoptosis displays all features of bona fide programmed cell death
and is inhibited by RXR, but not RAR antagonists. Several types of
survival signals block rexinoid-induced apoptosis. RARα agonists
switch the cellular response toward differentiation and induce the
expression of antiapoptosis factors. Activation of the protein kinase
A pathway in the presence of rexinoid agonists induces
maturation and blocks immature cell apoptosis. Addition of nonretinoid
serum factors also blocks cell death but does not induce cell
differentiation. Rexinoid-induced apoptosis is linked to neither
the presence nor stability of the promyelocytic
leukemia-RARα fusion protein and operates also in non-acute
promyelocytic leukemia cells. Together our results support a model
according to which rexinoids activate in certain leukemia cells
a default death pathway onto which several other signaling paradigms
converge. This pathway is entirely distinct from that triggered by RAR
agonists, which control cell maturation and postmaturation apoptosis.