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

Petroni, Marialaura; Veschi, Veronica; Prodosmo, Andrea; Rinaldo, Cinzia; Massimi, Isabella; Carbonari, Maurizio; Dominici, Carlo; McDowell, Heather P.; Rinaldi, Christian; Screpanti, Isabella; Frati, Luigi; Bartolazzi, Armando; Gulino, Alberto; Soddu, Silvia; Giannini, Giuseppe

doi:10.1158/1541-7786.mcr-10-0227

Cited by 33 publications

(48 citation statements)

References 51 publications

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“…1h). Further, analysis of the p53 phosphorylation status revealed a lower phosphorylation level of the serine 46 residue in MycN(-) cells, which is in agreement with recently published data on the significance of p53 phosphorylation for apoptosis in MycN overexpressing cells [14]; the extent of phosphorylation was correlated with the level of total p53 (Fig. 1h).…”

Section: Downregulation Ofsupporting

confidence: 92%

Targeting mitochondria by α-tocopheryl succinate kills neuroblastoma cells irrespective of MycN oncogene expression

Kruspig

Nilchian

Bejarano

et al. 2012

Cell. Mol. Life Sci.

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Amplification of the MycN oncogene characterizes a subset of highly aggressive neuroblastomas, the most common extracranial solid tumor of childhood. However, the significance of MycN amplification for tumor cell survival is controversial, since down-regulation of MycN was found to decrease markedly neuroblastoma sensitivity towards conventional anticancer drugs, cisplatin, and doxorubicin. Here, we show that a redox-silent analogue of vitamin E, α-tocopheryl succinate (α-TOS), which triggers apoptotic cell death via targeting mitochondria, can kill tumor cells irrespective of their MycN expression level. In cells overexpressing MycN, as well as cells in which MycN was switched off, α-TOS stimulated rapid entry of Ca(2+) into the cytosol, compromised Ca(2+) buffering capacity of the mitochondria and sensitized them towards mitochondrial permeability transition and subsequent apoptotic cell death. Prevention of mitochondrial Ca(2+) accumulation or chelation of cytosolic Ca(2+) rescued the cells. Thus, targeting mitochondria might be advantageous for the elimination of tumor cells with otherwise dormant apoptotic pathways.

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Section: Downregulation Ofsupporting

confidence: 92%

Targeting mitochondria by α-tocopheryl succinate kills neuroblastoma cells irrespective of MycN oncogene expression

Kruspig

Nilchian

Bejarano

et al. 2012

Cell. Mol. Life Sci.

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“…p53 is actively involved in the apoptosis-sensitive phenotype induced by MYCN. Indeed, MYCN increases p53 transcription [20] and it also induces stabilization of the p53 protein and its proapoptotic kinase HIPK2 via an oncogene-dependent DNA damage response (DDR) [13]. The high levels of mitosis/karyorrhexis and the initial responses to the induction chemotherapy shown by the majority of newly diagnosed MNA NBs are consistent with the integrity of the HIPK2-p53 axis observed in primary NBs [13].…”

Section: Introductionmentioning

confidence: 66%

“…Studying this paradox is likely to uncover molecular mechanisms potentially relevant for the therapy of MNA NBs. Indeed, by these means several groups, including ours, highlighted the p53 pathway as a potential target for MNA NB therapy [13], [14], [15].…”

Section: Introductionmentioning

confidence: 77%

“…Indeed, MYCN increases p53 transcription [20] and it also induces stabilization of the p53 protein and its proapoptotic kinase HIPK2 via an oncogene-dependent DNA damage response (DDR) [13]. The high levels of mitosis/karyorrhexis and the initial responses to the induction chemotherapy shown by the majority of newly diagnosed MNA NBs are consistent with the integrity of the HIPK2-p53 axis observed in primary NBs [13]. Despite this, however, MNA NBs undergo a fast and lethal progression in most instances, and this might be related to genetic or functional inactivation of p53 [21].…”

Section: Introductionmentioning

confidence: 99%

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Galectin-3 Impairment of MYCN-Dependent Apoptosis-Sensitive Phenotype Is Antagonized by Nutlin-3 in Neuroblastoma Cells

et al. 2012

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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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“…We speculate that this might be due to the presence of the wild-type TP53 in RH18 cells. It was reported that MYCN can regulate TP53 transcription, expression, and activation in human neuroblastoma cells (40,44). For example, high TP53 expression was positively correlated with MYCN expression and amplification in immunohistochemical analysis of neuroblastoma tumors (45).…”

Section: (T) (T) 10 (N) and 1μm (N) For 1 3 And Days B: Sub-conmentioning

confidence: 96%

Sphingosine Induces Apoptosis and Down-regulation of MYCN in PAX3–FOXO1-positive Alveolar Rhabdomyosarcoma Cells Irrespective of TP53 Mutation

Ahn

Lee

Seo

et al. 2018

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Abstract. Background/Aim: Rhabdomyosarcoma is the most common type of pediatric soft-tissue sarcoma. Among the subsets of this disease, alveolar rhabdomyosarcoma (ARMS) expressing paired box 3 (PAX3) and forkhead box O1 (PAX3-FOXO1Rhabdomyosarcoma (RMS) is the most common type of pediatric soft tissue sarcoma and accounts for approximately 50% of all soft-tissue sarcomas (1). RMS occurs predominantly in the sites of skeletal muscle lineage. RMS is categorized into two subtypes based on histological observations (2); embryonal (ERMS) and alveolar (ARMS). Between these two subtypes, ARMS has the worse prognosis and is associated with a higher frequency of metastasis (3, 4). ARMS is characterized by the translocation t(2;13)(q35;q14) or t(1;13)(q36;q14) that lead to paired box 3-forkhead box O1 (PAX3-FOXO1) and paired box 7-forkhead box O1 (PAX7-FOXO1) gene fusions, respectively. PAX3-FOXO1 is present in about 55% of ARMS harboring overexpression of this fusion gene at both RNA and protein levels. PAX7-FOXO1 is present in 22% of ARMS, and the remaining 23% of ARMS is fusion-negative (3, 5). PAX3-FOXO1-positive ARMS is the most clinically intractable subtype among RMS types (2, 3, 6, 7). Mutation of tumor protein p53 (TP53) is infrequent in RMS, occurring in fewer than 10% of patients (8), and inactive TP53 is more common in fusion-negative RMS (9).Sphingolipids are practically ubiquitous and are found in all eukaryotic cell membranes, some prokaryotes, and in foods such as dairy and soy products (10, 11). Animal studies showed complex dietary sphingolipids (e.g. sphingomyelin, dihydrosphingomyelin, glucosylceramide, lactosylceramide, and ganglioside GD 3 ), reduced aberrant colonic foci in CF1 mice (12-17) and reduced tumors in all regions of the intestine in multiple intestinal neoplasia (Min) mice with truncated adenomatous polyposis coli (17, 18). These anti-tumorigenic effects of sphingolipids against colon carcinogenesis could be the result of the conversion of complex sphingolipids to sphingolipid metabolites. Sphingolipid metabolites, such as ceramide (acylated form of sphingosine) and sphingoid bases (sphingosine, 71

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

Cited by 33 publications

References 51 publications

Targeting mitochondria by α-tocopheryl succinate kills neuroblastoma cells irrespective of MycN oncogene expression

Targeting mitochondria by α-tocopheryl succinate kills neuroblastoma cells irrespective of MycN oncogene expression

Galectin-3 Impairment of MYCN-Dependent Apoptosis-Sensitive Phenotype Is Antagonized by Nutlin-3 in Neuroblastoma Cells

Sphingosine Induces Apoptosis and Down-regulation of MYCN in PAX3–FOXO1-positive Alveolar Rhabdomyosarcoma Cells Irrespective of TP53 Mutation

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