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Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumor-selective death ligand TRAIL

Nature Medicine volume 7, pages 680–686 (2001)Cite this article

Abstract

The therapeutic and preventive activities of retinoids in cancer are due to their ability to modulate the growth, differentiation, and survival or apoptosis of cancer cells. Here we show that in NB4 acute promyelocytic leukemia cells, retinoids selective for retinoic-acid receptor-α induced an autoregulatory circuitry of survival programs followed by expression of the membrane-bound tumor-selective death ligand, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand, also called Apo-2L). In a paracrine mode of action, TRAIL killed NB4 as well as heterologous and retinoic-acid–resistant cells. In the leukemic blasts of freshly diagnosed acute promyelocytic leukemia patients, retinoic-acid–induced expression of TRAIL most likely caused blast apoptosis. Thus, induction of TRAIL-mediated death signaling appears to contribute to the therapeutic value of retinoids.

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Figure 1: RAR-α agonists induce survival programs prior to apoptosis in promyelocytic NB4 cells.
Figure 2: In NB4 cells, ATRA activates a paracrine death program that induces apoptosis in breast-cancer and ATRA-resistant cells.
Figure 3: ATRA-induced expression of TRAIL in NB4 and PLB985 cells a, RPA to monitor the effect of ATRA on the expression of death receptors and death ligands.
Figure 4: ATRA-induced TRAIL expression in NB4 cells is the cause of apoptosis.
Figure 5: ATRA induces TRAIL expression in the blasts of APL patients and synergizes with exogenous TRAIL for induction of apoptosis.
Figure 6: Survival and death programs induced by ATRA through the PML–RAR-α oncoprotein in promyelocytic NB4 cells.

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Acknowledgements

We thank M. Lieb and E. Wilhelm for cell culture and FACS analysis; C. Erb and A. Pornon for cloning and analysis of the BCL2A1 promoter; N. Balitrand for handling of the patient samples F-1 and F-2; J.-Y. Chen on advice in using the RPA system; A.M. Molinari for providing the ATRA-treated blasts of patient I-1; M. Lanotte and G. Benoit for the NB4 and NB4-R2 cell lines; Y.E. Cayre for PLB985 cells; Genentech/Immunex for TRAIL cDNA; and Bristol-Myers Squibb for synthetic retinoids. This work was supported by funds from the Human Fronteir Science (A. Reitmair) and the Marie Curie (W.R.) programs, the ministere pour la Recherche et Technologie (A. Rossin), the Institut National de la Santé et de la Recherche Médicale, the Centre National de la Recherche Scientifique (L.A.), the Hôpital Universitaire de Strasbourg and Bristol-Myers Squibb.

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  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, C.U. de Strasbourg, France

    Lucia Altucci, Aurelie Rossin, Wolfgang Raffelsberger, Armin Reitmair & Hinrich Gronemeyer

  2. Institut d'hematology-LBCH, Hôpital St. Louis, Paris, France

    Christine Chomienne

  3. Istituto di Patologia Generale e Oncologia, Seconda Università degli Studi di Napoli, Napoli, Italy

    Lucia Altucci

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Correspondence to Hinrich Gronemeyer.

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Altucci, L., Rossin, A., Raffelsberger, W. et al. Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumor-selective death ligand TRAIL. Nat Med 7, 680–686 (2001). https://doi.org/10.1038/89050

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