Antineoplastic effects of rosiglitazone and PPARγ transactivation in neuroblastoma cells

Cellai, Ilaria; Benvenuti, Stefania; Luciani, Paola; Galli, Andrea; Ceni, E.; Simi, Lisa; Baglioni, Silvana; Muratori, Monica; Ottanelli, B.; Serio, Mario; Cj, Thiele; Peri, Alessandro

doi:10.1038/sj.bjc.6603344

Cited by 29 publications

(31 citation statements)

References 41 publications

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“…We demonstrated previously that RGZ determines a significant reduction in MMP-9 and a trend towards an increase in TIMP-1 expression in SK-N-AS cells (Cellai et al, 2006). In this study, we were able to determine the amount of mRNA of MMP-9 and TIMP-1 in the few residual tumour tissues that were available (n ¼ 3 for each group, i.e., RGZ-treated (4 weeks) or control mice).…”

Section: Mmp-9 and Timp-1 Expressionmentioning

confidence: 74%

“…The assay was performed as previously described (Cellai et al, 2006). Briefly, tissue samples were boiled and dissolved in 10% glycerol, 2% SDS, and 50 mM Tris -HCl (pH 7.5) for 10 min.…”

Section: Pparc Phosphorylation Assaymentioning

confidence: 99%

“…The PPARg expression was determined as previously described (Cellai et al, 2006). Briefly, tissue samples were dissolved in lysis buffer.…”

Section: Western Blot Analysis Of Pparc Expressionmentioning

confidence: 99%

“…In the recent past, it has been observed that in different NB cell lines expressing PPARg, endogenous or synthetic ligands induce anti-neoplastic effects such as cell differentiation, apoptosis, growth arrest, reduced viability and inhibition of invasiveness (Emmans et al, 2004;Servidei et al, 2004;Valentiner et al, 2005;Cellai et al, 2006;Peri et al, 2008).…”

mentioning

confidence: 99%

“…In particular, we have previously shown that PPARg agonist rosiglitazone (RGZ) exerts strong anti-neoplastic effects (i.e., inhibition of cell proliferation and cell viability, decrease of matrix metalloproteinase-9 (MMP-9) expression, inhibition of cell adhesion and invasiveness) in SK-N-AS but not in SH-SY5Y human NB cells (Cellai et al, 2006). We also demonstrated that the different efficacy of RGZ was related to the presence of a significantly higher transcriptional activity of PPARg in SK-N-AS compared with SH-SY5Y, which was most likely because of a markedly higher amount of phosphorylated, that is, inactive, PPARg in the latter cell line.…”

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confidence: 99%

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In vivo effects of rosiglitazone in a human neuroblastoma xenograft

et al. 2010

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BACKGROUND: Neuroblastoma (NB) is the most common extra-cranial solid tumour in infants. Unfortunately, most children present with advanced disease and have a poor prognosis. There is in vitro evidence that the peroxisome proliferator-activated receptor g (PPARg) might be a target for pharmacological intervention in NB. We have previously demonstrated that the PPARg agonist rosiglitazone (RGZ) exerts strong anti-tumoural effects in the human NB cell line, SK-N-AS. The aim of this study was to evaluate whether RGZ maintains its anti-tumoural effects against SK-N-AS NB cells in vivo. METHODS AND RESULTS: For this purpose, tumour cells were subcutaneously implanted in nude mice, and RGZ (150 mg kg À1 ) was administered by gavage daily for 4 weeks. At the end of treatment, a significant tumour weight inhibition (70%) was observed in RGZ-treated mice compared with control mice. The inhibition of tumour growth was supported by a strong anti-angiogenic activity, as assessed by CD-31 immunostaining in tumour samples. The number of apoptotic cells, as determined by cleaved caspase-3 immunostaining, seemed lower in RGZ-treated animals at the end of the treatment period than in control mice, likely because of the large tumour size observed in the latter group. CONCLUSIONS: To our knowledge, this is the first demonstration that RGZ effectively inhibits tumour growth in a human NB xenograft and our results suggest that PPARg agonists may have a role in anti-tumoural strategies against NB.

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Section: Mmp-9 and Timp-1 Expressionmentioning

confidence: 74%

“…The assay was performed as previously described (Cellai et al, 2006). Briefly, tissue samples were boiled and dissolved in 10% glycerol, 2% SDS, and 50 mM Tris -HCl (pH 7.5) for 10 min.…”

Section: Pparc Phosphorylation Assaymentioning

confidence: 99%

“…The PPARg expression was determined as previously described (Cellai et al, 2006). Briefly, tissue samples were dissolved in lysis buffer.…”

Section: Western Blot Analysis Of Pparc Expressionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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In vivo effects of rosiglitazone in a human neuroblastoma xenograft

et al. 2010

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The EWSR1/NR4A3 fusion protein of extraskeletal myxoid chondrosarcoma activates the PPARG nuclear receptor gene

Filion

Motoi

Olshen

et al. 2008

The Journal of Pathology

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The NR4A3 nuclear receptor is implicated in the development of extraskeletal myxoid chondrosarcoma (EMC), primitive sarcoma unrelated to conventional chondrosarcomas, through a specific fusion with EWSR1 resulting in an aberrant fusion protein that is thought to disrupt the transcriptional regulation of specific target genes. We performed an expression microarray analysis of EMC tumors expressing the EWSR1/NR4A3 fusion protein, comparing their expression profiles to those of other sarcoma types. We thereby identified a set of genes significantly over-expressed in EMC relative to other sarcomas, including PPARG and NDRG2. Western blot or immunohistochemical analyses confirm that PPARG and NDRG2 are expressed in tumors positive for EWSR1/NR4A3. Bioinformatic analysis identified a DNA response element for EWSR1/NR4A3 in the PPARG promoter, and band-shift experiments and transient transfections indicate that EWSR1/NR4A3 can activate transcription through this element. Western blots further show that an isoform of the native NR4A3 receptor lacking the C terminal domain is very highly expressed in tumors positive for EWSR1/NR4A3, and co-transfections of this isoform along with EWSR1/NR4A3 indicate that it may negatively regulate the activity of the fusion protein on the PPARG promoter. These results suggest that the overall expression of PPARG in EMC may be regulated in part by the balance between EWSR1/NR4A3 and NR4A3, and that PPARG may play a crucial role in the development of these tumors. The specific up-regulation of PPARG by EWSR1/NR4A3 may also have potential therapeutic implications.

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Neuroblastoma and Related Tumors

The Genetics and Molecular Biology of Neural Tumors

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Antineoplastic effects of rosiglitazone and PPARγ transactivation in neuroblastoma cells

Cited by 29 publications

References 41 publications

In vivo effects of rosiglitazone in a human neuroblastoma xenograft

In vivo effects of rosiglitazone in a human neuroblastoma xenograft

The EWSR1/NR4A3 fusion protein of extraskeletal myxoid chondrosarcoma activates the PPARG nuclear receptor gene

Neuroblastoma and Related Tumors

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