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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 RAR_α_ 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

RAR_α_ 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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your

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FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS CO-TARGETING LEUKEMIA-INITIATING CELLS AND LEUKEMIA BULK LEADS TO DISEASE ERADICATION Article 04 March 2022 PERTURBING

LSD1 AND WNT REWIRES TRANSCRIPTION TO SYNERGISTICALLY INDUCE AML DIFFERENTIATION Article Open access 16 April 2025 A NOVEL FUSION PROTEIN TBLR1-RARΑ ACTS AS AN ONCOGENE TO INDUCE MURINE

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and Vivat-Hannah V . (2002). _Drug Discov. Today_, 7, 1165–1174. Download references 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. AUTHOR INFORMATION Author notes * Tewfik Sahraoui Present address: Université d'Oran Es-Senia, Faculté de Biologie, B.P. 16, Oran, 31100, Algeria

AUTHORS AND AFFILIATIONS * 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 * INSERM U-362, Institut Gustave Roussy, 39 rue Camille Desmoulins, Villejuif, 94800, France Francois Delhommeau & 

Annelise Bennaceur-Griscelli Authors * Frédéric Pendino View author publications You can also search for this author inPubMed Google Scholar * Charles Dudognon View author publications You

can also search for this author inPubMed Google Scholar * Francois Delhommeau View author publications You can also search for this author inPubMed Google Scholar * Tewfik Sahraoui View

author publications You can also search for this author inPubMed Google Scholar * Maria Flexor View author publications You can also search for this author inPubMed Google Scholar * Annelise

Bennaceur-Griscelli View author publications You can also search for this author inPubMed Google Scholar * Michel Lanotte View author publications You can also search for this author

inPubMed Google Scholar * Evelyne Ségal-Bendirdjian View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Evelyne

Ségal-Bendirdjian. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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

Download citation * Received: 13 May 2003 * Revised: 02 August 2003 * Accepted: 05 August 2003 * Published: 11 December 2003 * Issue Date: 11 December 2003 * DOI:

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currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * telomerase * hTERT * retinoids * RAR * RXR * nuclear

receptors