The Role of MYCN in the Failure of MYCN Amplified Neuroblastoma Cell Lines to G1 Arrest After DNA Damage

Bell, Emma; Premkumar, Rakesh; Carr, Jane; Lü, Xiaohong; Lovat, Penny E.; Kees, Ursula R.; Lunec, John; Tweddle, Deborah A.

doi:10.4161/cc.5.22.3443

Cited by 46 publications

(56 citation statements)

References 21 publications

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“…Regarding MYCN amplification status, all the three resistant cell lines had MYCN amplification and three of four sensitive cell lines had single copy MYCN, suggesting that inactivity of p53 in the resistant cell lines may relate to the MYCN amplification. Consistent with our observation, Bell et al (2006) reported that MYCN amplification correlates with attenuated p21 Cip1/Waf1 induction in p53 wild-type NB cells. The analysis of the molecular mechanism between MYCN amplification and p53 inactivation in NB cells may be important for NB studies.…”

Section: Discussionsupporting

confidence: 92%

Stress via p53 pathway causes apoptosis by mitochondrial Noxa upregulation in doxorubicin-treated neuroblastoma cells

et al. 2007

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In this study, we employed a panel of cell lines to determine whether p53-dependent cell death in neuroblastoma (NB) cells is caused by apoptotic cellular function, and we further studied the molecular mechanism of apoptosis induced via the p53-dependent pathway. We obtained evidence that a type of p53-dependent stress, doxorubicin (Doxo) administration, causes accumulation of p53 in the nucleus of NB cells and phosphorylation of several serine residues in both Doxo-sensitive and -resistant cell lines. Upregulation of p53-downstream molecules in cells and upregulation of Noxa in the mitochondrial fraction were observed only in Doxo-sensitive NB cells. Significance of Noxa in the Doxo-induced NB cell death was confirmed by Noxa-knockdown experiments. Mitochondrial dysfunction, including cytochrome-c release and membrane potential disregulation, occurred and resulted in the activation of the intrinsic caspase pathway. However, in the Doxo-resistant cells, the accumulation in the nucleus and phosphorylation of p53 did not induce p53-downstream p21 Cip1/Waf1 expression and the Noxa upregulation, resulting in the retention of the mitochondrial homeostasis. Taken together, these findings indicate that the p53 pathway seems to play a crucial role in NB cell death by Noxa regulation in mitochondria, and inhibition of the induction of p53-downstream effectors may regulate drug resistance of NB cells.

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Section: Discussionsupporting

confidence: 92%

Stress via p53 pathway causes apoptosis by mitochondrial Noxa upregulation in doxorubicin-treated neuroblastoma cells

et al. 2007

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“…1A). The MNA, but p53-mutant, SK-N-BE2c cells represented once again a sharp exception, whereas among the MNSC cells the highest HIPK2 expression was detected in SY5Y cells, which are known to express relatively high levels of MYCN (21). HIPK2 transcript levels did not directly correlate with MNA or with HIPK2 protein levels, consistent with a nontranscriptional regulation of its expression by MYCN (not shown).…”

Section: Hipk2 Is Expressed and Required For Bleomycininduced Apoptosmentioning

confidence: 69%

“…Indeed, primary MNA neuroblastomas are not insensitive to radio-and chemotherapy, at diagnosis. Consistent with this, MNA does not correlate with drug resistance in vitro (20) and MNA cell lines retain a higher sensitivity to ionizing radiations (IR)-induced apoptosis compared with MNSC cells (21).…”

Section: Introductionmentioning

confidence: 65%

“…Very recently, MYCN was shown to transcriptionally regulate p53 expression (23), leading to the hypothesis that p53 upregulation might be involved in MYCN-dependent sensitization to apoptosis. However, p53 induction was reproducibly shown to occur at similar levels in MYCNoverexpressing and -nonoverexpressing neuroblastoma cells, on treatment with clastogenic drugs (21,24) suggesting that, although necessary, p53 expression might not be sufficient for the induction of apoptosis in neuroblastoma cells. Additional mechanisms might contribute to the MYCN-dependent sensitization to apoptosis, some of which might be directly linked to p53 activation via post-translational modifications.…”

Section: Introductionmentioning

confidence: 99%

“…MNA neuroblastomas are sensitive to chemo-or radiotherapy at diagnosis and MNA neuroblastoma cell lines were shown to be more sensitive to IR-induced apoptosis than MNSC cells (20,21). In keeping with these observations, a short pulse of the radiomimetic drug bleomycin induced apoptosis more efficiently in MNA neuroblastoma cells (i.e., LAN-5, IMR32, GILIN, and KCNR) compared with MNSC cells (i.e., GIMEN, SK-N-SH, and SHEP) as indicated by dead cell count and PARP cleavage (cPARP; Fig.…”

Section: Mycn Sensitizes Neuroblastoma Cells To Apoptosis Induced By mentioning

confidence: 99%

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MYCN Sensitizes Human Neuroblastoma to Apoptosis by HIPK2 Activation through a DNA Damage Response

Petroni

Veschi

Prodosmo

et al. 2011

Molecular Cancer Research

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MYCN amplification occurs in approximately 20% of human neuroblastomas and is associated with early tumor progression and poor outcome, despite intensive multimodal treatment. However, MYCN overexpression also sensitizes neuroblastoma cells to apoptosis. Thus, uncovering the molecular mechanisms linking MYCN to apoptosis might contribute to designing more efficient therapies for MYCN-amplified tumors. Here we show that MYCN-dependent sensitization to apoptosis requires activation of p53 and its phosphorylation at serine 46. The p53 S46 kinase HIPK2 accumulates on MYCN expression, and its depletion by RNA interference impairs p53 S46 phosphorylation and apoptosis. Remarkably, MYCN induces a DNA damage response that accounts for the inhibition of HIPK2 degradation through an ATM-and NBS1-dependent pathway. Prompted by the rare occurrence of p53 mutations and by the broad expression of HIPK2 in our human neuroblastoma series, we evaluated the effects of the p53-reactivating compound Nutlin-3 on this pathway. At variance from other tumor histotypes, in MYCN-amplified neuroblastoma, Nutlin-3 further induced HIPK2 accumulation, p53 S46 phosphorylation, and apoptosis, and in combination with clastogenic agents purged virtually the entire cell population. Altogether, our data uncover a novel mechanism linking MYCN to apoptosis that can be triggered by the p53-reactivating compound Nutlin-3, supporting its use in the most difficult-to-treat subset of neuroblastoma.

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COX2 expression in neuroblastoma increases tumorigenicity but does not affect cell death in response to the COX2 inhibitor celecoxib

Bell

Ponthan

Whitworth

et al. 2014

Clin Exp Metastasis

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COX2 is an inducible cyclooxygenase implicated in the metastasis and migration of tumour cells. In neuroblastoma, COX2 expression has been detected in both cell lines and tumours. The treatment of neuroblastoma cells in vitro with celecoxib, a COX2 inhibitor, induces apoptosis. The aim of this study was to investigate the role of COX2 in neuroblastoma tumour biology by creating a cell line in which COX2 could be conditionally expressed. Xenograft studies showed that the conditional expression of COX2 enhanced tumour growth and malignancy. Elevated COX2 expression enhanced the proliferation and migration of neuroblastoma cells in vitro. However, elevated COX2 expression or variation between cell lines did not affect sensitivity to the COX2 inhibitor celecoxib, indicating that celecoxib does not promote cell death through COX2 inhibition. These data show that increased COX2 expression alone can enhance the tumorigenic properties of neuroblastoma cells; however, high levels of COX2 may not be a valid biomarker of sensitivity to non-steroidal anti-inflammatory drugs such as celecoxib.

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The Role of MYCN in the Failure of MYCN Amplified Neuroblastoma Cell Lines to G1 Arrest After DNA Damage

Cited by 46 publications

References 21 publications

Stress via p53 pathway causes apoptosis by mitochondrial Noxa upregulation in doxorubicin-treated neuroblastoma cells

Stress via p53 pathway causes apoptosis by mitochondrial Noxa upregulation in doxorubicin-treated neuroblastoma cells

MYCN Sensitizes Human Neuroblastoma to Apoptosis by HIPK2 Activation through a DNA Damage Response

COX2 expression in neuroblastoma increases tumorigenicity but does not affect cell death in response to the COX2 inhibitor celecoxib

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