Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies show that the MYCN and MDM2-p53 signal pathways are mutually regulated: MYCN stimulates MDM2 and p53 transcription, whereas MDM2 stabilizes MYCN mRNA and induces its translation. Herein, we report that the interaction between MDM2 and MYCN plays a critical role in MYCN-amplified neuroblastoma tumor cell growth and survival. Distinct from the known role that MDM2 has in regulating tumor promotion in non-MYCN-amplified neuroblastoma, in which MDM2 inhibits p53, we found that MDM2 stimulated tumor growth in MYCN-amplified neuroblastoma in a p53-independent manner. In MYCN-amplified neuroblastoma cells, enforced expression of MDM2 further enhanced MYCN expression, yet no p53 inhibition was observed by MDM2 due to upregulation of MYCN that stimulated p53 transcription. Similarly, p53 expression remained unchanged in MDM2-silenced MYCN-amplified neuroblastoma cells because MDM2 inhibition resulted in a downregulation of MYCN that decreased p53 transcription, although the MDM2-mediated degradation of p53 was reduced. Also, we found that the enforced overexpression of MDM2, or conversely, the inhibition of overexpressed endogenous MDM2, led to either a remarkable increase or decrease in tumor growth, respectively, in MYCN-amplified neuroblastoma (even though no p53 function was involved). These results suggest that p53 that is reciprocally regulated by MDM2 and MYCN is dispensable for suppression of MYCN-amplified neuroblastoma, and that the direct interaction between MDM2 and MYCN may contribute significantly to MYCN-amplified neuroblastoma growth and disease progression.
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PMID:Crosstalk between MYCN and MDM2-p53 signal pathways regulates tumor cell growth and apoptosis in neuroblastoma. 2186 76

Expression of vascular endothelial growth factor (VEGF) increases in cancer cells during hypoxia. Herein, we report that the MDM2 oncoprotein plays a role in hypoxia-mediated VEGF upregulation. In studying the characteristics of MDM2 and VEGF expression in neuroblastoma cells, we found that hypoxia induced significantly higher upregulation of both VEGF mRNA and protein in MDM2-positive cells than in the MDM2-negative cells, even in cells without wild-type (wt) p53. We found that hypoxia induced translocation of MDM2 from the nucleus to the cytoplasm, which was associated with increased VEGF expression. Enforcing overexpression of cytoplasmic MDM2 by transfection of the mutant MDM2/166A enhanced expression of VEGF mRNA and protein production, even without hypoxia. The results of mechanistic studies demonstrated that the C-terminal RING domain of the MDM2 protein bound to the AU-rich sequence within the 3' untranslated region (3'UTR) of VEGF mRNA; this binding increased VEGF mRNA stability and translation. In addition, knockdown of MDM2 by small interfering RNA (siRNA) in MDM2-overexpressing cancer cells resulted in inhibition of VEGF protein production, cancer cell survival, and angiogenesis. Our results suggest that MDM2 plays a p53-independent role in the regulation of VEGF, which may promote tumor growth and metastasis.
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PMID:MDM2 regulates vascular endothelial growth factor mRNA stabilization in hypoxia. 2198

Arsenite treatment of human SH-SY5Y neuroblastoma cells leads to an upregulation of caspase-3/7 activity and to the fragmentation of chromatin that is accompanied by elevated p53 and c-Jun levels. Expression of a truncated mutant of p53, p53DD, which interfered with the oligomerization of p53, suppressed the arsenite-induced upregulation of caspase-3/7 activity and the fragmentation of chromatin, indicating that p53 is required for arsenite-induced cell death. These data were corroborated by knockdown experiments of p53 following expression of a p53-specific short hairpin RNA. Likewise, expression of either p53DD or knockdown of p53 prevented caspase-3/7 activation and chromatin fragmentation induced by nutlin-3, a compound that prevents the interaction between p53 and the E3 ubiquitin ligase MDM2. Transcriptional upregulation of a chromatin-embedded p53-responsive reporter gene in either arsenite or nutlin-3 stimulated neuroblastoma cells revealed that the transcriptional activity of p53 was increased under these conditions. Expression of a c-Jun-specific short hairpin RNA failed to impair arsenite-induced caspase-3/7 activation and fragmentation of chromatin. Likewise, inhibition of c-Jun target gene expression by expression of a dominant-negative mutant of c-Jun did not interfere with arsenite-induced caspase-3/7 activation and chromatin fragmentation. However, this approach successfully reduced caspase-3/7 activity induced as a result of forced expression of a constitutively active mutant of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase (MEKK)-1. Together, these data show that the upregulation of p53 is causally linked with arsenite-induced cell death in neuroblastoma cells, whereas the upregulation of c-Jun is not part of this apoptotic signaling cascade.
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PMID:Arsenite-induced apoptosis of human neuroblastoma cells requires p53 but occurs independently of c-Jun. 2226 Aug 69

The p53 oncosuppressor is very seldom mutated in neuroblastoma, but several mechanisms cooperate to its functional inactivation in this tumor. Increased MDM2 levels, due to genetic amplification or constitutive inhibition of p14( ARF), significantly contribute to this event highlighting p53 reactivation as an attractive perspective for neuroblastoma treatment. In addition to its role in tumorigenesis, MYCN sensitizes untransformed and cancer cells to apoptosis. This is associated to a fine modulation of the MDM2-p53 pathway. Indeed MYCN induces p53 and MDM2 transcription, and, by evoking a DNA damage response (DDR), it stabilizes p53 and its proapoptotic kinase Homeodomain Interacting Protein Kinase 2 (HIPK2). Through the regulation of the HIPK2-p53 inhibitor High Mobility Group protein A1 (HMGA1) and the homeobox proteins BMI-1 and TWIST-1, MYCN establishes a delicate balance between pro- and antiapoptotic molecules that might be easily perturbed by a variety of insults, leading to cell death. MDM2-p53 antagonists, such as Nutlin-3, are strikingly prone to inducing death in MYCN-amplified neuroblastoma, by further pushing on HIPK2 accumulation. Here we discuss implications and caveats of exploiting this pathway and its connections to MYCN-induced DDR for a tailored therapy of MYCN-amplified neuroblastoma.
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PMID:Molecular mechanisms of MYCN-dependent apoptosis and the MDM2-p53 pathway: an Achille's heel to be exploited for the therapy of MYCN-amplified neuroblastoma. 2309 2

MYCN amplification occurs in about 20-25% of human neuroblastomas and characterizes the majority of the high-risk cases, which display less than 50% prolonged survival rate despite intense multimodal treatment. Somehow paradoxically, MYCN also sensitizes neuroblastoma cells to apoptosis, understanding the molecular mechanisms of which might be relevant for the therapy of MYCN amplified neuroblastoma. We recently reported that the apoptosis-sensitive phenotype induced by MYCN is linked to stabilization of p53 and its proapoptotic kinase HIPK2. In MYCN primed neuroblastoma cells, further activation of both HIPK2 and p53 by Nutlin-3 leads to massive apoptosis in vitro and to tumor shrinkage and impairment of metastasis in xenograft models. Here we report that Galectin-3 impairs MYCN-primed and HIPK2-p53-dependent apoptosis in neuroblastoma cells. Galectin-3 is broadly expressed in human neuroblastoma cell lines and tumors and is repressed by MYCN to induce the apoptosis-sensitive phenotype. Despite its reduced levels, Galectin-3 can still exert residual antiapoptotic effects in MYCN amplified neuroblastoma cells, possibly due to its specific subcellular localization. Importantly, Nutlin-3 represses Galectin-3 expression, and this is required for its potent cell killing effect on MYCN amplified cell lines. Our data further characterize the apoptosis-sensitive phenotype induced by MYCN, expand our understanding of the activity of MDM2-p53 antagonists and highlight Galectin-3 as a potential biomarker for the tailored p53 reactivation therapy in patients with high-risk neuroblastomas.
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PMID:Galectin-3 impairment of MYCN-dependent apoptosis-sensitive phenotype is antagonized by nutlin-3 in neuroblastoma cells. 2315 63

The TP53 tumor suppressor pathway is abrogated by TP53 mutations in the majority of human cancers. Increased levels of wild-type TP53 in aggressive neuroblastomas appear paradox but are tolerated by tumor cells due to co-activation of the TP53 ubiquitin ligase, MDM2. The role of the MDM2 antagonist, p14(ARF), in controlling the TP53-MDM2 balance in neuroblastoma is unresolved. In the present study, we show that conditional p14(ARF) expression substantially suppresses viability, clonogenicity and anchorage-independent growth in p14(ARF)-deficient or MYCN-amplified neuroblastoma cell lines. Furthermore, ectopic 14(ARF) expression induced accumulation of cells in the G1 phase and apoptosis, which was paralleled by accumulation of TP53 and its targets. Comparative genomic hybridization analysis of 193 primary neuroblastomas detected one homozygous deletion of CDKN2A (encoding both p14(ARF) and p16(INK4A)) and heterozygous loss of CDKN2A in 22% of tumors. Co-expression analysis of p14(ARF) and its transactivator, E2F1, in a set of 68 primary tumors revealed only a weak correlation, suggesting that further regulatory mechanisms govern p14(ARF) expression in neuroblastomas. Intriguingly, analyses utilizing chromatin immunoprecipitation revealed different histone mark-defined epigenetic activity states of p14(ARF) in neuroblastoma cell lines that correlated with endogenous p14(ARF) expression but not with episomal p14(ARF) promoter reporter activity, indicating that the native chromatin context serves to epigenetically repress p14(ARF) in neuroblastoma cells. Collectively, the data pinpoint p14(ARF) as a critical factor for efficient TP53 response in neuroblastoma cells and assign p14(ARF) as a neuroblastoma suppressor candidate that is impaired by genomic loss and epigenetic repression.
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PMID:Low p14ARF expression in neuroblastoma cells is associated with repressed histone mark status, and enforced expression induces growth arrest and apoptosis. 2334 16

Relapse with drug-resistant disease is the main cause of death in MYCN-amplified neuroblastoma patients. MYCN-amplified neuroblastoma cells in vitro are characterized by a failure to arrest at the G(1)-S checkpoint after irradiation- or drug-induced DNA damage. We show that several MYCN-amplified cell lines harbor additional chromosomal aberrations targeting p53 and/or pRB pathway components, including CDK4/CCND1/MDM2 amplifications, p16INK4A/p14ARF deletions or TP53 mutations. Cells with these additional aberrations undergo significantly lower levels of cell death after doxorubicin treatment compared with MYCN-amplified cells, with no additional mutations in these pathways. In MYCN-amplified cells CDK4 expression is elevated, increasing the competition between CDK4 and CDK2 for binding p21. This results in insufficient p21 to inhibit CDK2, leading to high CDK4 and CDK2 kinase activity upon doxorubicin treatment. CDK4 inhibition by siRNAs, selective small compounds or p19(INK4D) overexpression partly restored G(1)-S arrest, delayed S-phase progression and reduced cell viability upon doxorubicin treatment. Our results suggest a specific function of p19(INK4D), but not p16(INK4A), in sensitizing MYCN-amplified cells with a functional p53 pathway to doxorubicin-induced cell death. In summary, the CDK4/cyclin D-pRB axis is altered in MYCN-amplified cells to evade a G(1)-S arrest after doxorubicin-induced DNA damage. Additional chromosomal aberrations affecting the p53-p21 and CDK4-pRB axes compound the effects of MYCN on the G(1) checkpoint and reduce sensitivity to cell death after doxorubicin treatment. CDK4 inhibition partly restores G(1)-S arrest and sensitizes cells to doxorubicin-mediated cell death in MYCN-amplified cells with an intact p53 pathway.
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PMID:CDK4 inhibition restores G(1)-S arrest in MYCN-amplified neuroblastoma cells in the context of doxorubicin-induced DNA damage. 2346 84

Neuroblastoma (NB) is a common pediatric cancer and contributes to more than 15% of all pediatric cancer-related deaths. Unlike adult tumors, recurrent somatic mutations in NB, such as tumor protein 53 (p53) mutations, occur with relative paucity. In addition, p53 downstream function is intact in NB cells with wild-type p53, suggesting that reactivation of p53 may be a viable therapeutic strategy for NB treatment. Herein, we report that the ubiquitin-specific protease 7 (USP7) inhibitor, P22077, potently induces apoptosis in NB cells with an intact USP7-HDM2-p53 axis but not in NB cells with mutant p53 or without human homolog of MDM2 (HDM2) expression. In this study, we found that P22077 stabilized p53 by inducing HDM2 protein degradation in NB cells. P22077 also significantly augmented the cytotoxic effects of doxorubicin (Dox) and etoposide (VP-16) in NB cells with an intact USP7-HDM2-p53 axis. Moreover, P22077 was found to be able to sensitize chemoresistant LA-N-6 NB cells to chemotherapy. In an in vivo orthotopic NB mouse model, P22077 significantly inhibited the xenograft growth of three NB cell lines. Database analysis of NB patients shows that high expression of USP7 significantly predicts poor outcomes. Together, our data strongly suggest that targeting USP7 is a novel concept in the treatment of NB. USP7-specific inhibitors like P22077 may serve not only as a stand-alone therapy but also as an effective adjunct to current chemotherapeutic regimens for treating NB with an intact USP7-HDM2-p53 axis.
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PMID:USP7 inhibitor P22077 inhibits neuroblastoma growth via inducing p53-mediated apoptosis. 2413 31

A peculiar feature of several types of childhood cancer is that loss-of-function mutations of the TP53 (p53) tumor suppressor gene are uncommon, in contrast to many adult tumors. As p53 needs to be inactivated in order for tumor cells to survive and thrive, pediatric tumors typically make use of other mechanisms to keep p53 in check. One of the critical negative regulators of p53 is the MDM2 oncoprotein. Many anticancer drug development efforts in the past decade have therefore been devoted to the discovery and optimization of small molecules that selectively disrupt the interaction between MDM2 and p53, which could provide, in principle, a potent means to restore p53 function in tumor cells with wild-type p53. The nutlins are the class of selective inhibitors of the p53-MDM2 interaction that are currently most advanced in their clinical development. We review here the preclinical data that support the potential therapeutic use of nutlin drugs in the treatment of various pediatric tumors, including neuroblastoma, retinoblastoma, osteosarcoma, Ewing's sarcoma, rhabdomyosarcoma, medulloblastoma, and childhood acute lymphoblastic leukemia.
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PMID:Pharmacologic activation of wild-type p53 by nutlin therapy in childhood cancer. 2426 62

Chemotherapy induces apoptosis and tumor regression primarily through activation of p53-mediated transcription. Neuroblastoma is a p53 wild type malignancy at diagnosis and repression of p53 signaling plays an important role in its pathogenesis. Recently developed small molecule inhibitors of the MDM2-p53 interaction are able to overcome this repression and potently activate p53 dependent apoptosis in malignancies with intact p53 downstream signaling. We used the small molecule MDM2 inhibitor, Nutlin-3a, to determine the p53 drug response signature in neuroblastoma cells. In addition to p53 mediated apoptotic signatures, GSEA and pathway analysis identified a set of p53-repressed genes that were reciprocally over-expressed in neuroblastoma patients with the worst overall outcome in multiple clinical cohorts. Multifactorial regression analysis identified a subset of four genes (CHAF1A, RRM2, MCM3, and MCM6) whose expression together strongly predicted overall and event-free survival (p<0.0001). The expression of these four genes was then validated by quantitative PCR in a large independent clinical cohort. Our findings further support the concept that oncogene-driven transcriptional networks opposing p53 activation are essential for the aggressive behavior and poor response to therapy of high-risk neuroblastoma.
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PMID:A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma. 2434 3


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