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Bexarotene Via CBP/P300 Induces Suppression of NF-Kb– Dependent Cell Growth and Invasion in Thyroid Cancer

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Bexarotene Via CBP/P300 Induces Suppression of NF-Kb– Dependent Cell Growth and Invasion in Thyroid Cancer Published OnlineFirst December 5, 2011; DOI: 10.1158/1078-0432.CCR-11-0510 Clinical Cancer Cancer Therapy: Preclinical Research Bexarotene via CBP/p300 Induces Suppression of NF-kB– Dependent Cell Growth and Invasion in Thyroid Cancer Audrey Cras1,2,3,Beatrice Politis1,2, Nicole Balitrand1,2,3, Diane Darsin-Bettinger1,2,3, Pierre Yves Boelle4,5,6, Bruno Cassinat1,2,3, Marie-Elisabeth Toubert3, and Christine Chomienne1,2,3 Abstract Purpose: Retinoic acid (RA) treatment has been used for redifferentiation of metastatic thyroid cancer with loss of radioiodine uptake. The aim of this study was to improve the understanding of RA resistance and investigate the role of bexarotene in thyroid cancer cells. Experimental Design: A model of thyroid cancer cell lines with differential response to RA was used to evaluate the biological effects of retinoid and rexinoid and to correlate this with RA receptor levels. Subsequently, thyroid cancer patients were treated with 13-cis RA and bexarotene and response evaluated on radioiodine uptake reinduction on posttherapy scan and conventional imaging. Results: In thyroid cancer patients, 13-cis RA resistance can be bypassed in some tumors by bexarotene. A decreased tumor growth without differentiation was observed confirming our in vitro data. Indeed, we show that ligands of RARs or RXRs exert different effects in thyroid cancer cell lines through either differentiation or inhibition of cell growth and invasion. These effects are associated with restoration of RARb and RXRg levels and downregulation of NF-kB targets genes. We show that bexarotene inhibits the transactivation potential of NF-kB in an RXR-dependent manner through decreased promoter permissiveness without interfering with NF-kB nuclear translocation and binding to its responsive elements. Inhibition of transcription results from the release of p300 coactivator from NF-kB target gene promoters and subsequent histone deacetylation. Conclusion: This study highlights dual mechanisms by which retinoids and rexinoids may target cell tumorigenicity, not only via RARs and RXRs, as expected, but also via NF-kB pathway. Clin Cancer Res; 18(2); 442–53. Ó2011 AACR. Introduction ablative doses of radioiodine, and suppressive treatment. The follow-up is based on measuring serum thyroglobulin Thyroid cancers are the most common malignancy of (TG) and imaging with radioiodine (RI) therapeutic scans. endocrine organs (1). Well-differentiated thyroid carcino- It has been estimated that about 20% of these patients will mas (DTC) derived from follicular cells account for around develop a local or distant recurrence. In some cases, TG and 80% of thyroid cancers and include papillary thyroid cancer RI scan are discordant, suggesting the presence of thyroid (PTC) and follicular thyroid cancer (FTC), respectively, cancer metastases which have lost the ability to trap RI (2). which are differentiated on the basis of histologic para- This is challenging for thyroid cancer management, as meters. Most of these cancers have an excellent prognosis anatomical localization of recurrences cannot be assessed and can be effectively managed by total thyroidectomy, and treatment with RI therapeutic doses is not effective, predicting a poorer outcome. Signaling through growth factors and their receptors and Authors' Affiliations: 1INSERM U490, F-75475, Paris, 2Universite Paris Diderot, Sorbonne Paris Cite, IUH, UMRS 940, F-75475, Paris, 3AP-HP, defects in regulation of cell-cycle control elements are Hôpital Saint Louis, F-75475, Paris, 4INSERM U707, F-75475, Paris, considered essential for cancer cell proliferation. Recent 5Universite Pierre et Marie Curie, Sorbonne Universites, UMRS 707, advances have improved the understanding of the thyroid F-75005 Paris, 6AP-HP, Hopital^ Saint Antoine, F-75005, Paris, France oncogenesis. Inappropriate activation of the mitogen-acti- Note: Supplementary data for this article are available at Clinical Cancer vated protein kinase pathway effectors may lead to tumor Research Online (http://clincancerres.aacrjournals.org/). initiation and transformation. Indeed, mutations or rear- Corresponding Author: Christine Chomienne, UMR-S 940, INSERM, rangements of tyrosine kinase receptor (RET and NTRK1), Universite Denis Diderot, Institut Universitaire d'Hematologie, Hopital^ Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France. Phone: BRAF, and Ras are found in most of thyroid cancers (3). 33-0-1-42-49-42-34; Fax: 33-0-1-53-72-40-16; E-mail: Cancer progression is associated with a loss of the differ- [email protected] entiated characteristics that define mature follicular thyroid doi: 10.1158/1078-0432.CCR-11-0510 cells with the full capacity for normal physiologic function Ó2011 American Association for Cancer Research. such as iodine uptake. Iodine is transported across the 442 Clin Cancer Res; 18(2) January 15, 2012 Downloaded from clincancerres.aacrjournals.org on October 2, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst December 5, 2011; DOI: 10.1158/1078-0432.CCR-11-0510 Bexarotene Represses NF-kB Signaling toma by various natural and synthetic retinoids (10), and Translational Relevance the transcriptional control of the normal RARA gene expres- sion by all-trans RA (ATRA) treatment in acute promyelo- After thyroidectomy, monitoring and treatment of cytic leukemia cells (11). RA efficacy in patients with thyroid thyroid cancer metastases relies on the uptake of radio- cancer is supported by in vitro data, showing that retinoids active iodine by the malignant thyroid cells. Unfortu- induce upregulation of RARb and differentiation of cells, nately, some patients have signs of relapse with no accompanied by the upregulation of NIS and TG expression detectable metastases on radioiodine whole-body scan. and DIO1 activity (12, 13). Treatment with 13-cis RA was This has been attributed to an absence of sodium iodide shown to restore RI uptake in thyroid cancer patients in symporter (NIS) and subsequent loss of iodine uptake. clinical trials (14–16). However, only one-third of the Retinoids, inducers of differentiation during embryo- patients respond, and further trials have failed to confirm genesis, are equally important for thyroidogenesis and 13-cis RA efficacy in these patients (17, 18). A clinical study NIS and the 50-deiodase genes are retinoic acid target showed that treatment with bexarotene, a RXR agonist can genes. We confirm previous reports of the ability of induce a radioiodine uptake by metastases in some patients retinoids to restore differentiation in thyroid cancer in (19, 20). These data prompted for a better understanding of vitro and in vivo and present novel data showing that RA signaling pathways and resistance in thyroid cancer cells. retinoid-resistant cells and patients may respond to We have previously reported that lack of RA responsive- rexinoids via inhibition of cell growth and invasion. ness in a FTC cell line was attributable to an altered histone This results from the decrease of NF-kB target gene acetylation pattern and could be relieved by combination of expression by modification of promoter permissiveness. ATRA and trichostatin A, a histone deacetylase inhibitor, This highlights a novel mechanism by which bexarotene underscoring the ongoing clinical trials based on differen- may control cancer progression. tiation and transcriptional therapy combination (21). To investigate the role of RXR agonist in these patients, we took advantage of the RA-resistant thyroid cancer cell line, FTC238, derived from the metastasis of the patient whose basolateral plasma cell membrane of thyrocytes via the cells, at diagnosis, allowed the establishment of the RA- þ À NA /I (sodium iodine) symporter (NIS; ref. 4). NIS and sensitive FTC133 cell line (22). In this study, we show that other proteins linked to the synthesis of thyroid hormones, ligands of RARs or RXRs exert different effects in thyroid such as TG, thyroid peroxydase (TPO), and type I iodothyr- cancer cells through either differentiation or inhibition of onine 50-deiodinase (DIO1) have been reported to be growth and invasion and may thus provide different ther- poorly expressed in thyroid cancer patients (5). Reduced apeutic approaches in DTC patients. Drug effects were expression of these differentiation proteins results from Ras associated with restoration of RARB and RXRG levels. Inter- mutations and alterations of transcription factors involved estingly, bexarotene inhibits the transactivation potential of in thyroid differentiation such as loss of TTF1 expression or NF-kB through the involvement of nuclear coactivator chromosomal translocation of paired box 8 (PAX8) with p300, without interfering with either nuclear translocation peroxisome proliferator-activated receptor gamma (PPARg; or binding of p65 to NF-kB–responsive elements. This study refs. 6, 7). highlights in a given cancer dual mechanisms by which Retinoids, a group of structural and functional derivatives retinoids may target cell tumorigenicity, not only via targets of vitamin A are known to regulate a large number of of retinoids such as RARs and RXRs, as expected, but also via essential biological processes, such as cell growth, differen- targets of the NF-kB pathway. tiation, and death. The effects are mainly mediated by 2 types of nuclear receptors—retinoic acid (RA) receptors Materials and Methods (RARs) and retinoid X receptors (RXRs)—which act as ligand-dependent transcription factors. By qualitative Reagents and chemicals mRNA detection
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