Vitamin A Research Today is a free monthly online journal that collates and summarizes the latest research about Vitamin A, including details on retinol, benefits, dosage, supplements, deficiency, information.

Retinoid-induced activation of NF-kappaB in APL cells is not essential for granulocytic differentiation, but prolongs the life span of mature cells.

Mathieu J, Giraudier S, Lanotte M, Besançon F

INSERM U685, Centre Hayem, Hôpital St Louis, 1 avenue Claude Vellefaux, 75475 Paris, France.

All-trans retinoic acid (ATRA) significantly improves the survival of patients with acute promyelocytic leukemia (APL) by inducing granulocytic differentiation of leukemia cells. Since an activation of the transcription factor NF-kappaB occurs during ATRA-induced maturation of APL cells, a mechanistic link between these two processes was investigated. Using an in vitro model for APL, we report that ectopic overexpression of a repressor of NF-kappaB activation did not affect granulocytic differentiation. Importantly, NF-kappaB inhibition markedly resulted in a decreased viability of the differentiated cells, which correlated with increased apoptosis. Apoptosis was accompanied by a sustained activation of the c-Jun N-terminal kinase (JNK). Inhibition of JNK by the specific inhibitor SP600125 or by transfection of a dominant-negative mutant of JNK1 reduced the percentage of apoptotic cells, thus showing that JNK activation constitutes a death signal. Furthermore, impairment of NF-kappaB activation resulted in increased levels of reactive oxygen species (ROS) upon ATRA treatment. ROS accumulation was suppressed by the antioxidant butylated hydroxyanisol, which also abolished ATRA-induced JNK activation and apoptosis. Altogether, our results demonstrate an anti-apoptotic effect of NF-kappaB activation during ATRA-induced differentiation of NB4 cells and identify repression of ROS-mediated JNK activation as a mechanism for this effect. Our observations also suggest that NF-kappaB signalling may contribute to an accumulation of mature APL cells and participate in the development of ATRA syndrome.

Published 3 November 2005 in Oncogene, 24(48): 7145-55.
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