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Retinoic acid receptor α and retinoid-X receptor-specific agonists synergistically target telomerase expression and induce tumor cell death

Oncogene volume 22, pages 9142–9150 (2003)Cite this article

Abstract

Retinoids modulate growth and differentiation of cancer cells through activation of gene transcription via the nuclear retinoic-acid receptors (RAR) and retinoid-X receptors (RXR). Their use in differentiation therapy of acute promyelocytic leukemia (APL) represents a model concept for reprogramming cancer cells. However, they also regulate antiproliferative genes whose functions do not mechanistically concur to this program. Recently, we have shown that, independently of maturation, a long-term all-trans retinoic acid (ATRA) treatment of the maturation-resistant APL cell line (NB4-LR1) represses telomerase (hTERT), leading to telomere shortening and death. Using retinoid-receptor-specific agonists, we demonstrate herein that cross-talk between RARα and RXR dual-liganded to their respective agonists resulted in strong synergistic downregulation of hTERT and subsequent cell death. Importantly, unlike ATRA, this synergy was obtained at very low agonist concentrations and occurred in other ATRA maturation-resistant APL cells. These findings provide the first demonstration that dual-liganded RXR and RARα signaling should allow efficient targeting of telomerase in differentiation-resistant tumor cells. Such a combination therapy might hold promise in clinic to avoid side effects of ATRA whose administration can indiscriminately activate all RARs. Given the tissue-specific expression of RARs, a tissue-selective therapy targeting telomerase in tumor cells by synthetic agonists can be envisioned.

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Acknowledgements

We wish to express our gratitude to the late Dr S Michel (Galderma R&D, Sophia-Antipolis, France) for providing the RAR agonists (Am580, CD666, CD2314) and the RXR agonist (CD3640). We thank Dr H Gronemeyer (Illkirch, France) for the RXR agonist (SR11237). We are grateful to Dr R Weinberg (Massachusetts Institute of Technology) for provision of the pBABE-puro-hTERT construct and to Drs KA Westerman and P Leboulch (Genetix Pharmaceuticals, Cambridge, MA, USA) for providing us with the lentiviral plasmids. This work was financed by INSERM, the Ligue contre le Cancer, and Association pour la Recherche contre le Cancer (ARC #4513 and #5707). MF was funded by the Association Claude Bernard, FP by the Ministère de la Recherche et de la Technologie and TS by the Coopération Franco-Algérienne. FP acknowledges the support of Société Française du Cancer.

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Author notes

  1. Tewfik Sahraoui

    Present address: Université d'Oran Es-Senia, Faculté de Biologie, B.P. 16, Oran, 31100, Algeria

Authors and Affiliations

  1. INSERM U496, Institut d'Hématologie, Hôpital Saint-Louis, 1, Avenue Claude Vellefaux, Paris, 75010, France

    Frédéric Pendino, Charles Dudognon, Tewfik Sahraoui, Maria Flexor, Michel Lanotte & Evelyne Ségal-Bendirdjian

  2. INSERM U-362, Institut Gustave Roussy, 39 rue Camille Desmoulins, Villejuif, 94800, France

    Francois Delhommeau & Annelise Bennaceur-Griscelli

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  1. Frédéric Pendino
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Correspondence to Evelyne Ségal-Bendirdjian.

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Pendino, F., Dudognon, C., Delhommeau, F. et al. Retinoic acid receptor α and retinoid-X receptor-specific agonists synergistically target telomerase expression and induce tumor cell death. Oncogene 22, 9142–9150 (2003). https://doi.org/10.1038/sj.onc.1207093

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