Down-Regulation of the Tumor Suppressor Gene Retinoic Acid Receptor β2 through the Phosphoinositide 3-Kinase/Akt Signaling Pathway

Lefebvre, Bruno; Brand, Céline; Flajollet, Sébastien; Lefèbvre, Philippe

doi:10.1210/me.2005-0321

Cited by 37 publications

(28 citation statements)

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“…Finally, PGE 2 did not suppress the enhanced growth-inhibitory and apoptosis-inducing effects of the ATRA and celecoxib combination. Meanwhile, a study reported by Bruno Lefebvre proved that the phosphoinositide 3-kinase/Akt signaling pathway caused an increased tethering of the corepressor silencing mediator for retinoic and thyroid hormone receptors (SMRT) to the RARβ promoter, down-regulated the RARβ expression, and impaired cellular differentiation in response to the retinoid in P19 and HeLa Cells [26]. A study conducted by Schroeder discovered that even 5 µM of celecoxib could reduce phosphorylation levels of Akt and its direct downstream substrate GSK-3β in lung cancer cell lines, and the effects were augmented by a combination of celecoxib and 4HPR [12].…”

Section: Discussionmentioning

confidence: 99%

Celecoxib increases retinoid sensitivity in human colon cancer cell lines

Liu

Zheng

et al. 2010

Cellular and Molecular Biology Letters

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Abstract:Retinoid resistance has limited the clinical application of retinoids as differentiation-inducing and apoptosis-inducing drugs. This study was designed to investigate whether celecoxib, a selective COX-2 inhibitor, has effects on retinoid sensitivity in human colon cancer cell lines, and to determine the possible mechanism of said effects. Cell viability was measured using the MTT assay. Apoptosis was detected via Annexin-V/PI staining and the flow cytometry assay. PGE 2 production was measured with the ELISA assay. The expression of RARβ was assayed via western blotting. The results showed that celecoxib enhanced the inhibitory effect of ATRA in both COX-2 high-expressing HT-29 and COX-2 low-expressing SW480 cell lines. Further study showed the ATRA and celecoxib combination induced greater apoptosis, but that the addition of PGE 2 did not affect the enhanced growth-inhibitory and apoptosis-inducing effects of the combination. Moreover, NS398 (another selective COX-2 inhibitor) did not affect the inhibitory effects of ATRA in the two cell lines. Western blotting showed that the expression of RARβ in HT-29 cell lines was increased by celecoxib, but not by NS398, and that the addition of PGE 2 did not affect the celecoxib-induced expression of the retinoic acid receptor beta. In conclusion, celecoxib increased the expression of RARβ and the level of cellular ATRA sensitivity through COX-2-independent mechanisms. This finding may provide a potential strategy for combination therapy.

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Section: Discussionmentioning

confidence: 99%

Celecoxib increases retinoid sensitivity in human colon cancer cell lines

Liu

Zheng

et al. 2010

Cellular and Molecular Biology Letters

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“…pSG5-hRAR, pSG5-hRXR, pSG5-hRXR, pSG5-hRXR, pSG5-hPPARγ (DR5)3-tk Luc, VP16-hRAR (PPRE)6-tk Luc, and Gal4-tk Luc were described elsewhere (58)(59)(60)(61) The pCMV-based human UCH-L1, USP22, and WWP2 expression vectors were purchased from OriGene.…”

Section: Methodsmentioning

confidence: 99%

Proteasomal degradation of retinoid X receptor α reprograms transcriptional activity of PPARγ in obese mice and humans

Lefebvre

Benomar²,

Guédin³

et al. 2010

J. Clin. Invest.

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Obese patients have chronic, low-grade inflammation that predisposes to type 2 diabetes and results, in part, from dysregulated visceral white adipose tissue (WAT) functions. The specific signaling pathways underlying WAT dysregulation, however, remain unclear. Here we report that the PPARγ signaling pathway operates differently in the visceral WAT of lean and obese mice. PPARγ in visceral, but not subcutaneous, WAT from obese mice displayed increased sensitivity to activation by its agonist rosiglitazone. This increased sensitivity correlated with increased expression of the gene encoding the ubiquitin hydrolase/ligase ubiquitin carboxyterminal esterase L1 (UCH-L1) and with increased degradation of the PPARγ heterodimerization partner retinoid X receptor α (RXRα), but not RXRβ, in visceral WAT from obese humans and mice. Interestingly, increased UCH-L1 expression and RXRα proteasomal degradation was induced in vitro by conditions mimicking hypoxia, a condition that occurs in obese visceral WAT. Finally, PPARγ-RXRβ heterodimers, but not PPARγ-RXRα complexes, were able to efficiently dismiss the transcriptional corepressor silencing mediator for retinoid and thyroid hormone receptors (SMRT) upon agonist binding. Increasing the RXRα/RXRβ ratio resulted in increased PPARγ responsiveness following agonist stimulation. Thus, the selective proteasomal degradation of RXRα initiated by UCH-L1 upregulation modulates the relative affinity of PPARγ heterodimers for SMRT and their responsiveness to PPARγ agonists, ultimately activating the PPARγ-controlled gene network in visceral WAT of obese animals and humans. IntroductionFrom a clinical perspective, visceral obesity predisposes to an increased incidence of type 2 diabetes mellitus (T2DM) and associated cardiovascular diseases (1, 2). The visceral white adipose tissue (visWAT; i.e., epididymal WAT) depot is believed to contribute to the low-grade, chronic inflammatory state that occurs in obese patients and animals and favors the progression toward T2DM. This feature stems from the specific functional properties of adipocytes from this WAT depot, which are highly sensitive to β-adrenergic stimulation and relatively resistant to the antilipolytic effects of insulin compared with subcutaneous adipocytes (3). Indeed, although subcutaneous WAT (scWAT; i.e., inguinal WAT) is predominantly, but not exclusively, a lipid storage tissue exhibiting a high adipocyte plasticity, visWAT also triggers complex endocrine regulations by releasing FFAs, hormones, and cytokines that reach the liver through the portal vein (reviewed in ref. 4). How visWAT functions are affected upon disease progression is unknown, but metabolic challenges increase the release of proinflammatory cytokines and decrease that of insulin-sensitizing adipokines by visWAT.Results from recent clinical trials (ADOPT, DREAM, and PRO-ACTIVE; ref. 5) indicate that the insulin-sensitizing thiazolidin-

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“…Early studies showed that loss of RAR-β 2 expression in some forms of cancer (e.g., NSCLC) resulted from chromosome 3p deletion [62]), but in others (e.g., head and neck cancer) neither homozygous deletions nor gene rearrangements have been found [34]. Since those findings were published, other studies have shown that transcriptional deregulation can silence RAR-β 2 expression through decreased levels of co-activators, the presence of corepressors, or epigenetic mechanisms such as histone deacetylation [63][64][65][66][67][68]. Expression of RAR-β 2 also depends on the cellular level of retinoids because this receptor is itself an RAinducible gene.…”

Section: Molecular Mechanisms Responsible For Loss Of Rar-β 2 Expressionmentioning

confidence: 99%

Tumor-suppressive activity of retinoic acid receptor-β in cancer

2007

Cancer Letters

119

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Retinoids, a group of structural and functional analogs of vitamin A, are known to regulate a large number of essential biological processes and to suppress carcinogenesis. The effects of retinoids are mainly mediated by nuclear retinoid receptors, which include retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Each receptor has three subtypes (α, β, and γ) and each subtype has different isoforms. Retinoic acid receptor-β (RAR-β) has four isoforms that have different affinities to retinoids and different biological functions. Loss of expression of RAR-β 2 during cancer development is associated with tumorigenesis and retinoid resistance; induction of its expression, on the other hand, can suppress carcinogenesis. Expression of another isoform, RAR-β 4 , is increased in various types of cancer. RAR-β 4 transgenic mice develop hyperplasia and neoplasia in various tissues, and induction of RAR-β 4 expression increases the growth of tumor cells that do not express RAR-β 2 . Future studies will focus on molecular pathways involving RAR-β 2 and the role of RAR-β 4 in cancer development.

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Down-Regulation of the Tumor Suppressor Gene Retinoic Acid Receptor β2 through the Phosphoinositide 3-Kinase/Akt Signaling Pathway

Cited by 37 publications

References 50 publications

Celecoxib increases retinoid sensitivity in human colon cancer cell lines

Celecoxib increases retinoid sensitivity in human colon cancer cell lines

Proteasomal degradation of retinoid X receptor α reprograms transcriptional activity of PPARγ in obese mice and humans

Tumor-suppressive activity of retinoic acid receptor-β in cancer

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