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Lindi Chen Rapha?l F. Rousseau Steven A. Middleton Gwen L. Nichols David R. Newell John Lunec Deborah A. Tweddle 《Oncotarget》2015,6(12):10207-10221
Neuroblastoma is a predominantly p53 wild-type (wt) tumour and MDM2-p53 antagonists offer a novel therapeutic strategy for neuroblastoma patients. RG7388 (Roche) is currently undergoing early phase clinical evaluation in adults. This study assessed the efficacy of RG7388 as a single-agent and in combination with chemotherapies currently used to treat neuroblastoma in a panel of neuroblastoma cell lines. RG7388 GI50 concentrations were determined in 21 p53-wt and mutant neuroblastoma cell lines of varying MYCN, MDM2 and p14ARF status, together with MYCN-regulatable Tet21N cells. The primary determinant of response was the presence of wt p53, and overall there was a >200-fold difference in RG7388 GI50 concentrations for p53-wt versus mutant cell lines. Tet21N MYCN+ cells were significantly more sensitive to RG7388 compared with MYCN− cells. Using median-effect analysis in 5 p53-wt neuroblastoma cell lines, selected combinations of RG7388 with cisplatin, doxorubicin, topotecan, temozolomide and busulfan were synergistic. Furthermore, combination treatments led to increased apoptosis, as evident by higher caspase-3/7 activity compared to either agent alone. These data show that RG7388 is highly potent against p53-wt neuroblastoma cells, and strongly supports its further evaluation as a novel therapy for patients with high-risk neuroblastoma and wt p53 to potentially improve survival and/or reduce toxicity. 相似文献
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Chemotherapy-Induced Apoptosis in a Transgenic Model of Neuroblastoma Proceeds Through p53 Induction 总被引:2,自引:2,他引:2
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Louis Chesler David D Goldenberg Rodney Collins Matt Grimmer Grace E Kim Tarik Tihan Kim Nguyen Slava Yakovenko Katherine K Matthay William A Weiss 《Neoplasia (New York, N.Y.)》2008,10(11):1268-1274
Chemoresistance in neuroblastoma is a significant issue complicating treatment of this common pediatric solid tumor. MYCN-amplified neuroblastomas are infrequently mutated at p53 and are chemosensitive at diagnosis but acquire p53 mutations and chemoresistance with relapse. Paradoxically, Myc-driven transformation is thought to require apoptotic blockade. We used the TH-MYCN transgenic murine model to examine the role of p53-driven apoptosis on neuroblastoma tumorigenesis and the response to chemotherapy. Tumors formed with high penetrance and low latency in p53-haploinsufficient TH-MYCN mice. Cyclophosphamide (CPM) induced a complete remission in p53 wild type TH-MYCN tumors, mirroring the sensitivity of childhood neuroblastoma to this agent. Treated tumors showed a prominent proliferation block, induction of p53 protein, and massive apoptosis proceeding through induction of the Bcl-2 homology domain-3-only proteins PUMA and Bim, leading to the activation of Bax and cleavage of caspase-3 and -9. Apoptosis induced by CPM was reduced in p53-haploinsufficient tumors. Treatment of MYCN-expressing human neuroblastoma cell lines with CPM induced apoptosis that was suppressible by siRNA to p53. Taken together, the results indicate that the p53 pathway plays a significant role in opposing MYCN-driven oncogenesis in a mouse model of neuroblastoma and that basal inactivation of the pathway is achieved in progressing tumors. This, in part, explains the striking sensitivity of such tumors to chemotoxic agents that induce p53-dependent apoptosis and is consistent with clinical observations that therapy-associated mutations in p53 are a likely contributor to the biology of tumors at relapse and secondarily mediate resistance to therapy. 相似文献
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《European journal of cancer (Oxford, England : 1990)》2014,50(8):1555-1565
Neuroblastoma (NB) is a paediatric solid tumour which originates from sympathetic nervous tissues. Deletions in chromosome 1p are frequently found in unfavourable NBs and are correlated with v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN) amplification; however, it remains to be elucidated how the 1p loss contributes to MYCN-related oncogenic processes in NB. In this study, we identified the role of Dnmt1-associated protein 1 (DMAP1), coded on chromosome 1p34, in the processes.We studied the expression and function of DMAP1 in NB and found that low-level expression of DMAP1 related to poor prognosis, unfavourable histology and 1p Loss of heterozygosity (LOH) of primary NB samples. Intriguingly, DMAP1 induced ataxia telangiectasia mutated (ATM) phosphorylation and focus formation in the presence of a DNA damage reagent, doxorubicin. By DMAP1 expression in NB and fibroblasts, p53 was activated in an ATM-dependent manner and p53-downstream pro-apoptotic Bcl-2 family molecules were induced at the mRNA level, resulting in p53-induced apoptotic death. BAX and p21Cip1/Waf1 promoter activity dependent on p53 was clearly up-regulated by DMAP1. Further, MYCN transduction in MYCN single-copy NB cells accelerated doxorubicin (Doxo)-induced apoptotic cell death; MYCN is implicated in DMAP1 protein stabilisation and ATM phosphorylation in these situations. DMAP1 knockdown attenuated MYCN-dependent ATM phosphorylation and NB cell apoptosis. Together, DMAP1 appears to be a new candidate for a 1p tumour suppressor and its reduction contributes to NB tumourigenesis via inhibition of MYCN-related ATM/p53 pathway activation. 相似文献
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Stefano J. Mandriota Linda J. Valentijn Laurence Lesne David R. Betts Denis Marino Mary Boudal-Khoshbeen Wendy B. London Anne-Laure Rougemont Edward F. Attiyeh John M. Maris Michael D. Hogarty Jan Koster Jan J. Molenaar Rogier Versteeg Marc Ansari Fabienne Gumy-Pause 《Oncotarget》2015,6(21):18558-18576
Neuroblastoma, a childhood cancer with highly heterogeneous biology and clinical behavior, is characterized by genomic aberrations including amplification of MYCN. Hemizygous deletion of chromosome 11q is a well-established, independent marker of poor prognosis. While 11q22-q23 is the most frequently deleted region, the neuroblastoma tumor suppressor in this region remains to be identified. Chromosome bands 11q22-q23 contain ATM, a cell cycle checkpoint kinase and tumor suppressor playing a pivotal role in the DNA damage response. Here, we report that haploinsufficiency of ATM in neuroblastoma correlates with lower ATM expression, event-free survival, and overall survival. ATM loss occurs in high stage neuroblastoma without MYCN amplification. In SK-N-SH, CLB-Ga and GI-ME-N human neuroblastoma cells, stable ATM silencing promotes neuroblastoma progression in soft agar assays, and in subcutaneous xenografts in nude mice. This effect is dependent on the extent of ATM silencing and does not appear to involve MYCN. Our findings identify ATM as a potential haploinsufficient neuroblastoma tumor suppressor, whose inactivation mirrors the increased aggressiveness associated with 11q deletion in neuroblastoma. 相似文献
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Sina Gogolin Richa Batra Nathalie Harder Volker Ehemann Tobias Paffhausen Nicolle Diessl Vitaliya Sagulenko Axel Benner Stephan Gade Ingo Nolte Karl Rohr Rainer König Frank Westermann 《Cancer letters》2013
High-risk neuroblastomas often harbor structural chromosomal alterations, including amplified MYCN, and usually have a near-di/tetraploid DNA index, but the mechanisms creating tetraploidy remain unclear. Gene-expression analyses revealed that certain MYCN/MYC and p53/pRB-E2F target genes, especially regulating mitotic processes, are strongly expressed in near-di/tetraploid neuroblastomas. Using a functional RNAi screening approach and live-cell imaging, we identified a group of genes, including MAD2L1, which after knockdown induced mitotic-linked cell death in MYCN-amplified and TP53-mutated neuroblastoma cells. We found that MYCN/MYC-mediated overactivation of the metaphase–anaphase checkpoint synergizes with loss of p53-p21 function to prevent arrest or apoptosis of tetraploid neuroblastoma cells. 相似文献
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Functional interplay between MYCN,NCYM, and OCT4 promotes aggressiveness of human neuroblastomas
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Yoshiki Kaneko Yusuke Suenaga S. M. Rafiqul Islam Daisuke Matsumoto Yohko Nakamura Miki Ohira Sana Yokoi Akira Nakagawara 《Cancer science》2015,106(7):840-847
Neuroblastoma is a pediatric solid tumor that originates from embryonic neural crest cells. The MYCN gene locus is frequently amplified in unfavorable neuroblastomas, and the gene product promotes the progression of neuroblastomas. However, the molecular mechanisms by which MYCN amplification contributes to stem cell‐like states of neuroblastoma remain elusive. In this study, we show that MYCN and its cis‐antisense gene, NCYM, form a positive feedback loop with OCT4, a core regulatory gene maintaining a multipotent state of neural stem cells. We previously reported that NCYM is co‐amplified with the MYCN gene in primary human neuroblastomas and that the gene product promotes aggressiveness of neuroblastoma by stabilization of MYCN. In 36 MYCN‐amplified primary human neuroblastomas, OCT4 mRNA expression was associated with unfavorable prognosis and was correlated with that of NCYM. The OCT4 protein induced both NCYM and MYCN in human neuroblastoma cells, whereas NCYM stabilized MYCN to induce OCT4 and stem cell‐related genes, including NANOG, SOX2, and LIN28. In sharp contrast to MYCN, enforced expression of c‐MYC did not enhance OCT4 expression in human neuroblastoma cells. All‐trans retinoic acid treatment reduced MYCN, NCYM, and OCT4 expression, accompanied by the decreased amount of OCT4 recruited onto the intron 1 region of MYCN. Knockdown of NCYM or OCT4 inhibited formation of spheres of neuroblastoma cells and promoted asymmetric cell division in MYCN‐amplified human neuroblastoma cells. These results suggest that the functional interplay between MYCN, NCYM, and OCT4 contributes to aggressiveness of MYCN‐amplified human neuroblastomas. 相似文献
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Van Maerken T Speleman F Vermeulen J Lambertz I De Clercq S De Smet E Yigit N Coppens V Philippé J De Paepe A Marine JC Vandesompele J 《Cancer research》2006,66(19):9646-9655
Circumvention of the p53 tumor suppressor barrier in neuroblastoma is rarely caused by TP53 mutation but might arise from inappropriately increased activity of its principal negative regulator MDM2. We show here that targeted disruption of the p53-MDM2 interaction by the small-molecule MDM2 antagonist nutlin-3 stabilizes p53 and selectively activates the p53 pathway in neuroblastoma cells with wild-type p53, resulting in a pronounced antiproliferative and cytotoxic effect through induction of G(1) cell cycle arrest and apoptosis. A nutlin-3 response was observed regardless of MYCN amplification status. Remarkably, surviving SK-N-SH cells adopted a senescence-like phenotype, whereas CLB-GA and NGP cells underwent neuronal differentiation. p53 dependence of these alternative outcomes of nutlin-3 treatment was evidenced by abrogation of the effects when p53 was knocked down by lentiviral-mediated short hairpin RNA interference. The diversity of cellular responses reveals pleiotropic mechanisms of nutlins to disable neuroblastoma cells and exemplifies the feasibility of exploiting, by a single targeted intervention, the multiplicity of anticancer activities exerted by a key tumor suppressor as p53. The observed treatment effects without the need of imposing a genotoxic burden suggest that selective MDM2 antagonists might be beneficial for treatment of neuroblastoma patients with and without MYCN amplification. 相似文献
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The p53 pathway and its inactivation in neuroblastoma 总被引:3,自引:0,他引:3
Tweddle DA Pearson AD Haber M Norris MD Xue C Flemming C Lunec J 《Cancer letters》2003,197(1-2):93-98
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Shunbin Xiong 《癌症》2013,(7):371-375
Mdm2 and Mdm4 are two key negative regulators of the tumor suppressor p53. Deletion of either Mdm2 or Mdm4 induces p53-dependent early embryonic lethality in knockout mouse models. The tissue-specific ... 相似文献
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Radosław Polański Aidan P. Noon Jeremy Blaydes Anna Phillips Carlos P. Rubbi Keith Parsons Nikolina Vlatković Mark T. Boyd 《Cancer letters》2014
Although the role of p53 as a tumour suppressor in renal cell carcinoma (RCC) is unclear, our recent analysis suggests that increased wild-type p53 protein expression is associated with poor outcome. A growing body of evidence also suggests that p53 expression and increased co-expression of MDM2 are linked with poor prognosis in RCC. We have therefore examined whether an MDM2 antagonist; Nutlin-3, might rescue/increase p53 expression and induce growth inhibition or apoptosis in RCC cells that retain wild-type p53. We show that inhibition of p53 suppression by MDM2 in RCC cells promotes growth arrest and p53-dependent senescence – phenotypes known to mediate p53 tumour suppression in vivo. We propose that future investigations of therapeutic strategies for RCC should incorporate MDM2 antagonism as part of strategies aimed at rescuing/augmenting p53 tumour suppressor function. 相似文献
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Regan PL Jacobs J Wang G Torres J Edo R Friedmann J Tang XX 《International journal of oncology》2011,38(1):105-112
Neuroblastoma is a childhood cancer that exhibits either a favorable or an unfavorable phenotype. MYCN and MYC are oncoproteins that play crucial roles in determining the malignancy of unfavorable neuroblastoma. The Hsp90 superchaperone complex assists in the folding and function of a variety of oncogenic client proteins. Inhibition of Hsp90 by small molecule inhibitors leads to the destabilization of these oncogenic proteins and consequently suppresses tumor malignancy. Nonetheless, little is known about the effect of Hsp90 inhibition on the stability of MYCN and MYC proteins. In this study, we investigated the effect of Hsp90 inhibition on the phenotype of unfavorable neuroblastoma cells including its effect on MYCN and MYC expression. Two MYCN-amplified neuroblastoma cell lines (IMR5 and CHP134) and two non-MYCN-amplified cell lines (SY5Y and SKNAS) were used to address the effect of Hsp90 inhibition on the malignant phenotype of neuroblastoma. It was found that Hsp90 inhibition in neuroblastoma cell lines resulted in significant growth suppression, a decrease in MYCN and MYC expression, and an increase in the expression of p53. In the TP53-mutated SKNAS cell line, Hsp90 inhibition enhanced the expression of the favorable neuroblastoma genes EFNB2, MIZ-1 and NTRK1 (TrkA). In addition, Hsp90 inhibition reduced HDAC6 expression and enhanced tubulin acetylation. Together our data suggest that Hsp90 inhibition suppresses the growth of neuroblastoma through multiple cellular pathways and that MYC/MYCN destabilization is among the important consequences of Hsp90 inhibition. 相似文献