MycN sensitizes neuroblastoma cells for drug-induced apoptosis

Fulda, Simone; Lutz, W; Schwab, Manfred; Debatin, Klaus‐Michael

doi:10.1038/sj.onc.1202435

Cited by 115 publications

(94 citation statements)

References 44 publications

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“…Of the pro-apoptotic molecules (Smac/DIABLO, Omi/HtrA2, and cytochrome c), cytochrome c binds to APAF-1 and forms the apoptosome complex together with procaspase-9, leading to caspase-9 activation and downstream events. Among the many ways for activated Myc to stimulate apoptosis are enabling activation of either Bax (at the mitochondria) or p53 (transcription of pro-apoptotic genes), or enhancing the Fas-mediated apoptosis signalling [122]. Anti-apoptotic Bcl-2 family members (Bcl-2, Bcl-X L , and Mcl-1) prevent mitochondrial pore formation and subsequent cytochrome c release, and are in turn inhibited by BH3-only molecules such as Bim.…”

Section: Apoptosis In the Developing Nervous Systemmentioning

confidence: 99%

“…Deregulated MYC expression has been reported to enhance tumour cell death in response to anti-cancer agents [121][122][123]. One pioneering study in this field showed that MYCN synergizes with the cytotoxic drug doxorubicin to promote apoptosis through upregulation of the Fas receptor, enhancing sensitivity to Fas ligand signalling, and induction of p53 and Bax protein expression [122].…”

Section: The Myc Protein Network and Apoptosismentioning

confidence: 99%

“…One pioneering study in this field showed that MYCN synergizes with the cytotoxic drug doxorubicin to promote apoptosis through upregulation of the Fas receptor, enhancing sensitivity to Fas ligand signalling, and induction of p53 and Bax protein expression [122]. In this way, MYCN targets both the extrinsic and the intrinsic pathway of apoptosis induction in response to drug treatment (Fig.…”

Section: The Myc Protein Network and Apoptosismentioning

confidence: 99%

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Embryonal neural tumours and cell death

et al. 2009

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Medulloblastoma and neuroblastoma are malignant embryonal childhood tumours of the central and peripheral nervous systems, respectively, which often show poor clinical prognosis due to resistance to current chemotherapy. Both these tumours have deficient apoptotic machineries adopted from their respective progenitor cells. This review focuses on the specific background for tumour development, and highlights biological pathways that present potential targets for novel therapeutic approaches.

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Section: Apoptosis In the Developing Nervous Systemmentioning

confidence: 99%

Section: The Myc Protein Network and Apoptosismentioning

confidence: 99%

Section: The Myc Protein Network and Apoptosismentioning

confidence: 99%

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Embryonal neural tumours and cell death

et al. 2009

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“…However, it has become apparent that N-myc also possesses a proapoptotic function. Exertion of the proapoptotic function of the myc family of proteins usually requires withdrawal of antiapoptotic survival factors such as serum deprivation (Ueda and Ganem, 1996;Jasty et al, 2001) or the application of a proapoptotic stimulus such as chemotherapy (Fulda et al, 1999). Since N-myc has functions of a tumor suppressor when subjected to these stressors, mechanisms protecting against cell death must be in place to allow N-myc to maintain its oncogenic function (Hogarty, 2003;Goldsmith and Hogarty, 2005).…”

Section: Introductionmentioning

confidence: 99%

N-myc augments death and attenuates protective effects of Bcl-2 in trophically stressed neuroblastoma cells

et al. 2008

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N-myc has proapoptotic functions, yet it acts as an oncogene in neuroblastoma. Thus, antiapoptotic mechanisms have to be operative in neuroblastoma cells that antagonize the proapoptotic effects of N-myc. We conditionally activated N-myc in SH-EP neuroblastoma cells subjected to the trophic stress of serum or nutrient deprivation while changing the expression of Bcl-2, survivin and FLIP L , antiapoptotic molecules often overexpressed in poor prognosis neuroblastomas. Bcl-2 protected SH-EP cells from death during nutritional deprivation by activating energetically advantageous oxidative phosphorylation. N-myc overrode the metabolic protection provided by Bcl-2-induced oxidative phosphorylation by reestablishing the glycolytic phenotype and attenuated the antiapoptotic effect of Bcl-2 during metabolic stress. Survivin partially antagonized the growth suppressive function of N-myc in SH-EP neuroblastoma cells during serum deprivation whereas FLIP L did not. These findings advance our understanding of the functions of N-myc in neuroblastoma cells.

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“…21,22 The above data and paradigm are well represented in cancer medicine by only one case, whereby it has been established that MYCN amplification represents a relatively good prognosis for neuroblastoma specifically in cases where the caspase 8 apoptosis-effector gene is present. [23][24][25][26][27] This case prompted us to readdress this issue but by focusing on activating mutations rather than amplification, particularly after having noted that there are patient cases where there are multiple oncoprotein mutations and other cases where cancer develops in the absence of any known oncoprotein mutation, a relatively unexpected situation considering the comprehensive wealth of knowledge known about the available oncoproteins and their considerable role in the theory of oncogenesis. The results for the analysis of the TCGA STAD set indicate that indeed, more oncoprotein mutations correlate with a more favorable outcome.…”

Section: Introductionmentioning

confidence: 99%

TCGA: Increased oncoprotein coding region mutations correlate with a greater expression of apoptosis-effector genes and a positive outcome for stomach adenocarcinoma

Yavorski

Blanck

2016

Cell Cycle

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Oncogene mutations are primarily thought to facilitate uncontrolled cell growth. However, overexpression of oncoproteins likely leads to apoptosis in a feed forward mechanism, whereby a certain level of oncoprotein leads to the activation of pro-proliferation effector genes and higher levels lead to activation of pro-apoptotic effector genes. TCGA STAD barcodes having no oncoprotein coding region mutations represented reduced expression of the apoptosis-effector genes compared with barcodes with multiple oncoprotein coding region mutations. Furthermore, STAD barcodes in a "no-subsequent tumor" group, representing 224 samples, and in a "positive outcome" group, had more oncoprotein coding regions mutated, on average, than barcodes of the new tumor and negative outcome groups, respectively. BRAF, CTNNB1, KRAS and MTOR coding region mutations (as a group) had the strongest association with the no-subsequent tumor group. Tumor suppressor coding region mutations were also correlated with no-subsequent tumor. These results are consistent with an oncoprotein-mediated, feed-forward mechanism of apoptosis in patients. Importantly, the nosubsequent tumor group also had more overall mutations. This result leads to considerations of unhealthy cells or cells with more neo-antigens for immune rejection. However, a probabilistic aspect of mutagenesis is also consistent with more oncoprotein and tumor suppressor protein mutations, in cases of more overall mutations, and thus a higher likelihood of activation of feed forward apoptosis pathways.

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MycN sensitizes neuroblastoma cells for drug-induced apoptosis

Cited by 115 publications

References 44 publications

Embryonal neural tumours and cell death

Embryonal neural tumours and cell death

N-myc augments death and attenuates protective effects of Bcl-2 in trophically stressed neuroblastoma cells

TCGA: Increased oncoprotein coding region mutations correlate with a greater expression of apoptosis-effector genes and a positive outcome for stomach adenocarcinoma

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