Identification and Pharmacological Inactivation of the MYCN Gene Network as a Therapeutic Strategy for Neuroblastic Tumor Cells

Chayka, Olesya; D’Acunto, Cosimo Walter; Middleton, Odette; Arab, Maryam; Sala, Arturo

doi:10.1074/jbc.m114.624056

Cited by 41 publications

(41 citation statements)

References 65 publications

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“…a, b, d, and e). Both activating and inactivating phosphorylations of CDC2, respectively, at Thr161 and Tyr15 [Nebreda, ; Chayka et al, ], were decreased in both investigated neuroblastoma cell lines overexpressing the wild‐type form of MCPIP1, as well as the mutant form MCPIP1‐ΔPIN, after normalization to reference protein—GAPDH (Fig. a, b, d, and e).…”

Section: Resultsmentioning

confidence: 99%

MCPIP1 Exogenous Overexpression Inhibits Pathways Regulating MYCN Oncoprotein Stability in Neuroblastoma

Boratyn

Nowak

Durbas

et al. 2017

J of Cellular Biochemistry

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The main physiological function of MCPIP1 (regnase-1) is negative regulation of inflammation. Moreover, roles of regnase-1 in apoptosis and differentiation have also been described, but its involvement in cancer is yet to be fully recognized. Earlier, we showed a lack of expression of MCPIP1 in both primary tumors and several neuroblastoma cell lines. Additionally, we reported that levels of MCPIP1 and the key neuroblastoma oncoprotein-MYCN were inversely correlated in BE(2)-C clones overexpressing the MCPIP1 gene. Here, we show that exogenous expression of the MCPIP1 protein decreases MYCN mRNA and protein levels without changing the MYCN mRNA half-life. Furthermore, it was shown that MCPIP1-wt exogenous expression affects levels and phosphorylation of MYCN partners such as Aurora A (Thr288), CDC2 (Tyr15 and Thr161), GSK3β (Ser9), and key cellular components of Akt/mTOR signaling, which regulate MYCN stability and activation. In accordance with the obtained results, we found increased phosphorylation of MYCN protein at Thr58 that causes destabilization of the oncoprotein. Moreover, it is shown that exogenous expression of MCPIP1 does not cause apoptosis. Our data extend knowledge on roles of MCPIP1 in our model and link the protein to regulation of expression and stability of MYCN through decrease of signaling via Akt/mTOR pathway. J. Cell. Biochem. 118: 1741-1755, 2017. © 2016 Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 99%

MCPIP1 Exogenous Overexpression Inhibits Pathways Regulating MYCN Oncoprotein Stability in Neuroblastoma

Boratyn

Nowak

Durbas

et al. 2017

J of Cellular Biochemistry

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“…Around 50% of HR-NB have an amplification of the MYCN oncogene, which drives proliferation and causes replication stress (117). MYCN also transcriptionally upregulates many proteins involved in DNA DSB repair, including components of the MRE11-RAD50-NBLS1 (MRN) complex (118,119), alternative NHEJ (alt-NHEJ) (120), and Bloom syndrome (BLM) helicase (121), and the cell cycle checkpoint protein CHK1 (117,122). Upregulation of these genes likely provide MYCNdriven tumors the ability to tolerate higher levels of DNA damage and replication stress.…”

Section: Ddr Defects In Neuroblastomamentioning

confidence: 99%

Targeting the DNA Damage Response for the Treatment of High Risk Neuroblastoma

et al. 2020

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Despite intensive multimodal therapy, the survival rate for high risk neuroblastoma (HR-NB) remains <50%. Most cases initially respond to treatment but almost half will subsequently relapse with aggressive treatment resistant disease. Novel treatments exploiting the molecular pathology of NB and/or overcoming resistance to current genotoxic therapies are needed before survival rates can significantly improve. DNA damage response (DDR) defects are frequently observed in HR-NB including allelic deletion and loss of function mutations in key DDR genes, oncogene induced replication stress and cell cycle checkpoint dysfunction. Exploiting defects in the DDR has been a successful treatment strategy in some adult cancers. Here we review the genetic features of HR-NB which lead to DDR defects and the emerging molecular targeting agents to exploit them.

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“…Inhibition of CKS1B is synthetically lethal with MYCN amplification/overexpression in neuroblastoma cells, suggesting that it may be used to target specifically MYC high tumours 12 . As RNA interference is not yet a viable option in cancer therapy, we used Prozac to disrupt the CKS1-SKP2 interaction, with the aim of causing stabilisation of the product of the tumour suppressor gene CDKN1B -P27 Kip1 -, in neuroblastoma cell lines.…”

Section: Expression In Neuroblastoma Cell Linesmentioning

confidence: 99%

“…Further studies have additionally shown that in neuroblastoma cells MYCN targets a separate Ebox location and, similarly to c-MYC, augments transcription of SKP2 11 . Furthermore, c-MYC and MYCN induce CKS1B transcription 10,12 . Targeting SKP2 causes p53-independent apoptosis in non-amplified neuroblastoma cells, whereas in MYCN-amplified cells it was noted a decrease in growth but not apoptosis 11 .…”

Section: Introductionmentioning

confidence: 99%

“…Likewise, when CKS1B was inhibited in tumour cells, apoptosis and growth arrest followed stabilisation of p27 Kip113,14 . A genome-wide, drop-out shRNA screen carried out in our laboratory has identified CKS1B as a potential therapeutic target gene in MYCN-amplified neuroblastoma by inducing synthetic lethality 12 . Although pharmacological inhibitors of SKP2 are not currently available 15 , CKS1 can be inhibited by a small molecule that is safe and available.…”

Section: Introductionmentioning

confidence: 99%

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Repurposing a psychoactive drug for children with cancer: p27Kip1-dependent inhibition of metastatic neuroblastomas by Prozac

et al. 2020

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The MYC family of transcription factors is a major driver of human cancer and potential therapeutic target. However, no clinically viable drugs have been yet developed that are able to directly tackle MYC oncoproteins. In our laboratory, we are exploring alternative approaches aiming to disturb signalling downstream of MYC. MYCN is frequently activated in neuroblastoma, a paediatric solid malignancy that, in its metastatic form, has a very poor prognosis. An important pathway regulated by MYC is the CKS1/SKP2/p27 kip1 axis. In this study, we have repurposed the anti-psychotic drug Prozac to disrupt CKS1/SKP2/p27 Kip1 signalling and assess its potential as an antineuroblastoma agent in vitro and in vivo. Using DNA editing technology, we show that stabilisation of p27 Kip1 operated by Prozac in MYC-activated cells is essential for the anti-neuroblastoma activity of the drug. Furthermore, dosing mice with a concentration of Prozac equivalent to that used in long-term clinical trials in children with psychiatric disorders caused a significant reduction of metastatic disease in two models of high-risk neuroblastoma. The favourable toxicity profile of Prozac suggests that long-term treatments might be implemented in children with MYC/CKS1 high neuroblastomas.

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Identification and Pharmacological Inactivation of the MYCN Gene Network as a Therapeutic Strategy for Neuroblastic Tumor Cells

Cited by 41 publications

References 65 publications

MCPIP1 Exogenous Overexpression Inhibits Pathways Regulating MYCN Oncoprotein Stability in Neuroblastoma

MCPIP1 Exogenous Overexpression Inhibits Pathways Regulating MYCN Oncoprotein Stability in Neuroblastoma

Targeting the DNA Damage Response for the Treatment of High Risk Neuroblastoma

Repurposing a psychoactive drug for children with cancer: p27Kip1-dependent inhibition of metastatic neuroblastomas by Prozac

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