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

Pendino, Frédéric; Dudognon, Charles; Delhommeau, François; Sahraoui, T.; Flexor, Maria; Bennaceur-Griscelli, Annelise; Lanotte, Michel; Ségal-Bendirdjian, Évelyne

doi:10.1038/sj.onc.1207093

Cited by 38 publications

(34 citation statements)

References 39 publications

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“…These retrovirally infected sublines have already been described. 27,29 In similar long-term treatments with ATRA and As 2 O 3 alone or in combination, NB4-LR1/hTERT-GFP and NB4-LR2/hTERT-GFP continued to proliferate without any change in cell viability (Figure 3). Even though NB4-LR1/hTERT-GFP cells demonstrated a reduced cell proliferation upon 40 days of ATRA/As 2 O 3 treatment, no loss of viability was detected.…”

Section: Resultsmentioning

confidence: 95%

“…The maturation-resistant human promyelocytic leukemia cell lines NB4-LR1 and NB4-LR2, 30,31 the selected subline NB4-LR1 SFD , 28 the retrovirally infected NB4-LR1/hTERT-GFP 27 and the NB4-LR2/hTERT-GFP sublines expressing both hTERT protein and the green fluorescent protein (GFP) reporter from the same transcript and the NB4-LR1/GFP and the NB4-LR2/GFP sublines expressing only the GFP control vector were cultured as described previously. [28][29][30] Both NB4-LR1 SFD and NB4-LR1/ hTERT-GFP sublines escape death induced by long-term ATRA treatment. 27,28 All cells were incubated at 371C in 5% CO 2 atmosphere (Binder Incubators).…”

Section: Methodsmentioning

confidence: 99%

“…[27][28][29] In NB4-LR1 cells, pharmacological concentrations of ATRA exhibit antiproliferative activities through the downregulation of telomerase, leading to telomere shortening and cell death. A synergistic repression of telomerase with subsequent cell death can also be obtained using synthetic RARa and RXR selective agonists not only in NB4-LR1 but also in NB4-LR2 cells.…”

Section: Introductionmentioning

confidence: 99%

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Retinoid/arsenic combination therapy of promyelocytic leukemia: induction of telomerase-dependent cell death

et al. 2005

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Acute promyelocytic leukemia (APL) is efficiently treated with a cell differentiation inducer, all-trans retinoic acid (ATRA). However, a significant percentage of patients still develop resistance to this treatment. Recently, arsenic trioxide (As 2 O 3 ), alone or in combination with ATRA, has been identified as an alternative therapy in patients with both ATRA-sensitive and ATRA-resistant APL. Previous investigations restricted the mechanism of this synergism to the modulation and/or degradation of PML-RARa oncoprotein through distinct pathways. In this study, using several ATRA maturation-resistant APL cell lines, we demonstrate in vitro that the success of ATRA/As 2 O 3 treatment in APL pathology can be explained, at least in part, by a synergistic effect of these two drugs in triggering downregulation of telomerase efficient enough to cause telomere shortening and subsequent cell death. Such long-term low-dose combinatorial therapy strategies, developed also to avoid acute side effects, reinforce the notion that the antitelomerase strategy, based on a combination of active agents, should now be considered and evaluated not only in APL but also in other malignancies.

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Section: Resultsmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Retinoid/arsenic combination therapy of promyelocytic leukemia: induction of telomerase-dependent cell death

et al. 2005

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“…Already existent evidence indicates that retinoids, through retinoid receptors, inhibit telomerase activity and downregulate hTERT expression. 36,37 These observations suggest that in the presence of the rs2075786 minor allele A, where a binding site for retinoid receptors is absent, natural retinoids cannot efficiently restrain hTERT expression, causing accelerated tumor cell growth.…”

Section: Rs2075786 and Telomere Lengthmentioning

confidence: 99%

Genetic variant in the telomerase gene modifies cancer risk in Lynch syndrome

et al. 2012

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Lynch syndrome (LS) is an inherited cancer-predisposing disorder caused by germline mutations in the mismatch repair (MMR) genes. The high variability in individual cancer risk observed among LS patients suggests the existence of modifying factors. Identifying genetic modifiers of risk could help implement personalized surveillance programs based on predicted cancer risks. Here we evaluate the role of the telomerase (hTERT) rs2075786 SNP as a cancer-risk modifier in LS, studying 255 and 675 MMR gene mutation carriers from Spain and the Netherlands, respectively. The study of the Spanish sample revealed that the minor allele (A) confers increased cancer risk at an early age. The analysis of the Dutch sample confirmed the association of the A allele, especially in homozygosity, with increased cancer risk in mutation carriers under the age of 45 (relative risk LScao45_AA ¼ 2.90; 95% confidence interval ¼ 1.02-8.26). Rs2075786 is associated with colorectal cancer (CRC) risk neither in the general population nor in non-Lynch CRC families. In silico studies predicted that the SNP causes the disruption of a transcription binding site for a retinoid receptor, retinoid X receptor alpha, probably causing early telomerase activation and therefore accelerated carcinogenesis. Notably, cancer-affected LS patients with the AA genotype have shorter telomeres than those with GG. In conclusion, MMR gene mutation carriers with hTERT rs2075786 are at high risk to develop a LS-related tumor at an early age. Cancer-preventive measures and stricter cancer surveillance at early ages might help prevent or early detect cancer in these mutation carriers.

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“…The maturation-resistant human APL cell lines, NB4-LR1 and the selected subline NB4-LR1 SFD , were cultured as previously described. [37][38][39][40] All cells were incubated at 37 1C at 5% CO 2 atmosphere (Binder Incubators, Nanterre, France). For treatment, cells were seeded at a density of 1-2 Â 10 5 cells/ml in medium supplemented with ATRA (1 mM).…”

Section: Chemicals and Cell Culturementioning

confidence: 99%

Epigenetic plasticity of hTERT gene promoter determines retinoid capacity to repress telomerase in maturation-resistant acute promyelocytic leukemia cells

Azouz

Hillion

et al. 2010

Leukemia

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The expression of hTERT gene, encoding the catalytic subunit of telomerase, is a feature of most cancer cells. Changes in the chromatin environment of its promoter and binding of transcriptional factors have been reported in differentiating cells when its transcription is repressed. However, it is not clear whether these changes are directly involved in this repression or only linked to differentiation. In a maturation-resistant acute promyelocytic leukemia (APL) cell line (NB4-LR1), we have previously identified a new pathway of retinoid-induced hTERT repression independent of differentiation. Using a variant of this cell line (NB4-LR1 SFD ), which resists to this repression, we show that although distinct patterns of histone modifications and transcription factor binding at the proximal domain of hTERT gene promoter could concur to modulate its expression, this region is not sufficient to the on/off switch of hTERT by retinoids. DNA methylation analysis of the hTERT promoter led to the identification of two distinct functional domains, a proximal one, fully unmethylated in both cell lines, and a distal one, significantly methylated in NB4-LR1 SFD cells, whose methylation was further re-enforced by retinoid treatment. Interestingly, we showed that the binding to this distal domain of a known hTERT repressor, WT1, was defective only in NB4-LR1 SFD cells. We propose that epigenetic modifications targeting this distal region could modulate the binding of hTERT repressors and account either for hTERT reactivation and resistance to retinoid-induced hTERT downregulation.

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

Cited by 38 publications

References 39 publications

Retinoid/arsenic combination therapy of promyelocytic leukemia: induction of telomerase-dependent cell death

Retinoid/arsenic combination therapy of promyelocytic leukemia: induction of telomerase-dependent cell death

Genetic variant in the telomerase gene modifies cancer risk in Lynch syndrome

Epigenetic plasticity of hTERT gene promoter determines retinoid capacity to repress telomerase in maturation-resistant acute promyelocytic leukemia cells

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