Cox-2-derived PGE<sub>2</sub>induces Id1-dependent radiation resistance and self-renewal in experimental glioblastoma

Cook, Peter J.; Thomas, Rozario; Kingsley, Philip J.; Shimizu, Fumiko; Montrose, David C.; Marnett, Lawrence J.; Tabar, Viviane; Dannenberg, Andrew J.; Benezra, Robert

doi:10.1093/neuonc/now049

Cited by 67 publications

(74 citation statements)

References 48 publications

(44 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with our results, E2F2 was found to have a protective role in radiation-induced, p53-independent apoptosis in Drosophila third-instar larvae (37). ID1 has recently been shown to be necessary for prostaglandin E2-mediated radiation resistance in mouse glioblastoma cells, and ID1 + human GSCs appear to be relatively radiation resistant (33). It is likely that additional NAD + -dependent consequences independent of E2F2 and ID1 also play a role in GSC radioresistance.…”

Section: Discussionsupporting

confidence: 89%

See 1 more Smart Citation

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

Gujar

Mao

et al. 2016

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

107

View full text Add to dashboard Cite

Accumulating evidence suggests cancer cells exhibit a dependency on metabolic pathways regulated by nicotinamide adenine dinucleotide (NAD + ). Nevertheless, how the regulation of this metabolic cofactor interfaces with signal transduction networks remains poorly understood in glioblastoma. Here, we report nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting step in NAD + synthesis, is highly expressed in glioblastoma tumors and patient-derived glioblastoma stem-like cells (GSCs). High NAMPT expression in tumors correlates with decreased patient survival. Pharmacological and genetic inhibition of NAMPT decreased NAD + levels and GSC self-renewal capacity, and NAMPT knockdown inhibited the in vivo tumorigenicity of GSCs. Regulatory network analysis of RNA sequencing data using GSCs treated with NAMPT inhibitor identified transcription factor E2F2 as the center of a transcriptional hub in the NAD + -dependent network. Accordingly, we demonstrate E2F2 is required for GSC selfrenewal. Downstream, E2F2 drives the transcription of members of the inhibitor of differentiation (ID) helix-loop-helix gene family. Finally, we find NAMPT mediates GSC radiation resistance. The identification of a NAMPT-E2F2-ID axis establishes a link between NAD + metabolism and a self-renewal transcriptional program in glioblastoma, with therapeutic implications for this formidable cancer.T he prognosis for glioblastoma, the most common malignant intrinsic brain tumor in adults, remains poor despite aggressive multidisciplinary therapy, including maximal safe surgical resection, radiation therapy, and temozolomide (1, 2). The failure of these interventions to generate a durable response stems in part from inadequate understanding of the metabolic and molecular mechanisms underlying malignant behavior and therapeutic resistance (3, 4). Nicotinamide adenine dinucleotide (NAD + ) has a well-known role in cellular metabolism and is an important cofactor for signaling pathways that regulate aging, inflammation, diabetes mellitus, axonal injury, and cancer (5, 6). Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD + synthesis, produces NAD + precursor nicotinamide mononucleotide (NMN) to drive NAD + -dependent processes. Interestingly, NAMPT expression is extremely low in the mammalian brain compared with other organs (7,8). However, NAMPT is highly expressed in several cancers, and features of cancer cells, including proliferation, invasion, and tumor growth, exhibit a dependence on NAD + (9-11). In noncancer cells, NAD + plays a critical role in transcriptional control, providing a metabolic basis for epigenetic reprogramming (12-16). Enzymes using NAD + as a cofactor, including the sirtuins and poly-ADP ribosyl transferases, regulate transcription factor activity and chromatin structure (13-15). Additionally, NAD + can control transcription by altering DNA methylation in neurons (12). However, in glioblastoma, little is known about NAD + -dependent transcriptional events and whether these even...

show abstract

Section: Discussionsupporting

confidence: 89%

“…The biological roles and mechanisms of ID family proteins in glioblastoma have been the subject of intense recent investigation (23,(33)(34)(35)(36). Benezra and colleagues (23) identified a self-renewing subpopulation expressing high levels of Id1 in a PDGFB-driven Arf −/− mouse model of glioblastoma.…”

Section: Discussionmentioning

confidence: 99%

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

Gujar

Mao

et al. 2016

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

107

View full text Add to dashboard Cite

show abstract

“…Indeed, overexpression of COX-2 or Id1 facilitated tumor progression in a mouse GBM model (Figure 4), whereas celecoxib and the genetic ablation of Id1 blocked COX-2 overactivation-mediated human GBM proliferation, migration, invasion, angiogenesis, and aggressiveness both in vitro and in vivo [45]. These findings suggest that COX-2 facilitates the malignant potential of human GBM at least partially through induction of Id1 and this is further supported by another recent study, in which COX-2-derived PGE 2 induced Id1 via EP4 receptor-dependent activation of mitogen-activated protein kinase (MAPK) signaling and another transcription factor, early growth response protein 1 (EGR-1) [79]. …”

Section: Preclinical Studiesmentioning

confidence: 75%

Cyclooxygenase-2 in glioblastoma multiforme

Jiang¹,

Shi²

2017

Drug Discovery Today

107

112

View full text Add to dashboard Cite

Glioblastoma multiforme (GBM) represents the most prevalent brain primary tumor, yet there is a lack of effective treatment. With current therapies, fewer than 5% of patients with GBM survive more than 5 years after diagnosis. Mounting evidence from epidemiological studies reveals that the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) is correlated with reduced incidence of GBM, suggesting that cyclooxygenase-2 (COX-2) and its major product within the brain, prostaglandin E2 (PGE2), are involved in the development and progression of GBM. Here, we highlight our current understanding of COX-2 in GBM proliferation, apoptosis, invasion, angiogenesis, and immunosuppression by focusing on recent in vitro and in vivo experimental data. We also discuss the feasibility of COX-2 as a therapeutic target for GBM in light of the latest human studies.

show abstract

“…4a,b)31. Interestingly, we did not observe activation of Caspase-3, suggesting that entrectinib does not induce apoptosis in Bcan-Ntrk1 -positive glioma cells (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 62%

Somatic chromosomal engineering identifies BCAN-NTRK1 as a potent glioma driver and therapeutic target

et al. 2017

Self Cite

View full text Add to dashboard Cite

The widespread application of high-throughput sequencing methods is resulting in the identification of a rapidly growing number of novel gene fusions caused by tumour-specific chromosomal rearrangements, whose oncogenic potential remains unknown. Here we describe a strategy that builds upon recent advances in genome editing and combines ex vivo and in vivo chromosomal engineering to rapidly and effectively interrogate the oncogenic potential of genomic rearrangements identified in human brain cancers. We show that one such rearrangement, an microdeletion resulting in a fusion between Brevican (BCAN) and Neurotrophic Receptor Tyrosine Kinase 1 (NTRK1), is a potent oncogenic driver of high-grade gliomas and confers sensitivity to the experimental TRK inhibitor entrectinib. This work demonstrates that BCAN-NTRK1 is a bona fide human glioma driver and describes a general strategy to define the oncogenic potential of novel glioma-associated genomic rearrangements and to generate accurate preclinical models of this lethal human cancer.

show abstract

Cox-2-derived PGE₂induces Id1-dependent radiation resistance and self-renewal in experimental glioblastoma

Cited by 67 publications

References 48 publications

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

Cyclooxygenase-2 in glioblastoma multiforme

Somatic chromosomal engineering identifies BCAN-NTRK1 as a potent glioma driver and therapeutic target

Contact Info

Product

Resources

About

Cox-2-derived PGE2induces Id1-dependent radiation resistance and self-renewal in experimental glioblastoma

Cited by 67 publications

References 48 publications

An NAD + -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

An NAD + -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

Cyclooxygenase-2 in glioblastoma multiforme

Somatic chromosomal engineering identifies BCAN-NTRK1 as a potent glioma driver and therapeutic target

Contact Info

Product

Resources

About

Cox-2-derived PGE₂induces Id1-dependent radiation resistance and self-renewal in experimental glioblastoma

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

An NAD ⁺ -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma