The Mechanism by Which MYCN Amplification Confers an Enhanced Sensitivity to a PCNA-Derived Cell Permeable Peptide in Neuroblastoma Cells

Gu, Leyi; Lingeman, Robert; McDaniel, Heather; Kechichian, Steven; Hickey, Robert J.; Liu, Zheng; Yuan, Yate-Ching; Sandoval, John A.; Fields, Gregg B.; Malkas, Linda H.

doi:10.1016/j.ebiom.2015.11.016

Cited by 28 publications

(29 citation statements)

References 56 publications

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“…These findings may have implications for future cancer prevention and therapeutic approaches targeting MYC-regulated metabolism. Unfortunately, however, finding small-molecule or biologic inhibitors of MYC has proved difficult because MYC is localized within the nucleus and does not have a deep surfacebinding pocket (33). Therefore, MYC is not amenable to blockade by small molecules or accessible to neutralization by antibodies.…”

Section: Discussionmentioning

confidence: 99%

Global metabolic reprogramming of colorectal cancer occurs at adenoma stage and is induced by MYC

Satoh

Yachida

Sugimoto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

294

256

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Cancer cells alter their metabolism for the production of precursors of macromolecules. However, the control mechanisms underlying this reprogramming are poorly understood. Here we show that metabolic reprogramming of colorectal cancer is caused chiefly by aberrant MYC expression. Multiomics-based analyses of paired normal and tumor tissues from 275 patients with colorectal cancer revealed that metabolic alterations occur at the adenoma stage of carcinogenesis, in a manner not associated with specific gene mutations involved in colorectal carcinogenesis. MYC expression induced at least 215 metabolic reactions by changing the expression levels of 121 metabolic genes and 39 transporter genes. Further, MYC negatively regulated the expression of genes involved in mitochondrial biogenesis and maintenance but positively regulated genes involved in DNA and histone methylation. Knockdown of MYC in colorectal cancer cells reset the altered metabolism and suppressed cell growth. Moreover, inhibition of MYC target pyrimidine synthesis genes such as CAD, UMPS, and CTPS blocked cell growth, and thus are potential targets for colorectal cancer therapy.ne of the prominent characteristics of rapidly growing tumor cells is their capacity to sustain high rates of glycolysis for ATP generation irrespective of oxygen availability, termed the Warburg effect (1). Recent studies have shown that cancer cells shift metabolic pathways to facilitate the uptake and incorporation of abundant nutrients, such as glucose and glutamine (2, 3), into cell building blocks, such as nucleotides, amino acids, and lipids, that are essential for highly proliferating cells (4). This seems to be a universal characteristic of highly malignant tumors (5), independent of their carcinogenetic origin (6). Understanding how cancer cells reprogram metabolism can stimulate the development of new approaches in cancer therapy.Although there is now substantial information about how these pathways are regulated, most existing studies on cancer metabolism have used in vitro cell lines. In addition to genetic and epigenetic alterations, altered tumor microenvironment (e.g., blood flow, oxygen and nutrient supply, pH distribution, redox state, and inflammation) plays a profound role in modulating tumor cell metabolism (7-9). Therefore, a systematic characterization of in vivo metabolic pathways was deemed necessary to understand how metabolic phenotypes are regulated in intact human tumors.Here we applied multiomics-based approaches [i.e., metabolomics, target sequencing of cancer-related genes, transcriptomics, and methylated DNA immunoprecipitation sequencing (MeDIPseq)] to paired normal and tumor tissues obtained from 275 patients with colorectal cancer (CRC) and uncovered the details of which factors contributed, and when they contributed, to metabolic reprogramming in colorectal cancer. The results were confirmed by analysis of colorectal tissue from Apc mutant mice and cancer cell lines.

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Section: Discussionmentioning

confidence: 99%

Global metabolic reprogramming of colorectal cancer occurs at adenoma stage and is induced by MYC

Satoh

Yachida

Sugimoto

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

294

256

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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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Section: Introductionmentioning

confidence: 99%

“…MYC proteins promote RS, DNA damage, and DDR by several mechanisms 24 – 31 . Increased levels of RS have been clearly detected in primary MNA tumors as compared to MYCN single copy (MNSC) samples 31 . Moreover, “DNA repair” is among the most significantly deregulated gene ontology groups in neuroblastomas sharing a MYCN signature 32 .…”

Section: Introductionmentioning

confidence: 99%

MRE11 inhibition highlights a replication stress-dependent vulnerability of MYCN-driven tumors

et al. 2018

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MRE11 is a component of the MRE11/RAD50/NBS1 (MRN) complex, whose activity is essential to control faithful DNA replication and to prevent accumulation of deleterious DNA double-strand breaks. In humans, hypomorphic mutations in these genes lead to DNA damage response (DDR)-defective and cancer-prone syndromes. Moreover, MRN complex dysfunction dramatically affects the nervous system, where MRE11 is required to restrain MYCN-dependent replication stress, during the rapid expansion of progenitor cells. MYCN activation, often due to genetic amplification, represents the driving oncogenic event for a number of human tumors, conferring bad prognosis and predicting very poor responses even to the most aggressive therapeutic protocols. This is prototypically exemplified by neuroblastoma, where MYCN amplification occurs in about 25% of the cases. Intriguingly, MRE11 is highly expressed and predicts bad prognosis in MYCN-amplified neuroblastoma. Due to the lack of direct means to target MYCN, we explored the possibility to trigger intolerable levels of replication stress-dependent DNA damage, by inhibiting MRE11 in MYCN-amplified preclinical models. Indeed, either MRE11 knockdown or its pharmacological inhibitor mirin induce accumulation of replication stress and DNA damage biomarkers in MYCN-amplified cells. The consequent DDR recruits p53 and promotes a p53-dependent cell death, as indicated by p53 loss- and gain-of-function experiments. Encapsulation of mirin in nanoparticles allowed its use on MYCN-amplified neuroblastoma xenografts in vivo, which resulted in a sharp impairment of tumor growth, associated with DDR activation, p53 accumulation, and cell death. Therefore, we propose that MRE11 inhibition might be an effective strategy to treat MYCN-amplified and p53 wild-type neuroblastoma, and suggest that targeting replication stress with appropriate tools should be further exploited to tackle MYCN-driven tumors.

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The Mechanism by Which MYCN Amplification Confers an Enhanced Sensitivity to a PCNA-Derived Cell Permeable Peptide in Neuroblastoma Cells

Cited by 28 publications

References 56 publications

Global metabolic reprogramming of colorectal cancer occurs at adenoma stage and is induced by MYC

Global metabolic reprogramming of colorectal cancer occurs at adenoma stage and is induced by MYC

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

MRE11 inhibition highlights a replication stress-dependent vulnerability of MYCN-driven tumors

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