Gamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated by the p75 Neurotrophin Receptor

Wang, Limei; Rahn, Jennifer J.; Lun, Xueqing; Sun, Beichen; Kelly, John J.; Weiss, Samuel; Robbins, Stephen M.; Forsyth, Peter; Senger, Donna L.

doi:10.1371/journal.pbio.0060289

Cited by 67 publications

(78 citation statements)

References 75 publications

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“…Recent studies of malignant gliomas found that inhibition of ␥-secretase cleavage of p75 results in a decrease in glioma invasion and an increase in survival (47). In this case, generation of the ICD in glioma cells produces a more invasive phenotype, suggesting that there are changes in gene expression as a result of p75 cleavage.…”

Section: Discussionmentioning

confidence: 99%

Nuclear Localization of the p75 Neurotrophin Receptor Intracellular Domain

Parkhurst

Zampieri

Chao

2010

Journal of Biological Chemistry

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The p75 neurotrophin receptor, a member of the tumor necrosis factor superfamily of receptors, undergoes an ␣-secretase-mediated release of its extracellular domain, followed by a ␥-secretase-mediated intramembrane cleavage. Like amyloid precursor protein and Notch, ␥-secretase cleavage of the p75 receptor releases an intracellular domain (ICD). However, it has been experimentally challenging to determine the precise subcellular localization and functional consequences of the p75 ICD. Here, we utilized a nuclear translocation assay and biochemical fractionation approaches to follow the fate of the ICD. We found that the p75 ICD can translocate to the nucleus to activate a green fluorescent protein reporter gene. Furthermore, the p75 ICD was localized in nuclear fractions. Chromatin immunoprecipitation experiments indicated that nerve growth factor induced the association of endogenous p75 with the cyclin E 1 promoter. Expression of the p75 ICD resulted in modulation of gene expression from this locus. These results suggest that the p75 ICD generated by ␥-secretase cleavage is capable of modulating transcriptional events in the nucleus.The p75 neurotrophin receptor is the founding member of the tumor necrosis factor receptor superfamily that includes the Fas antigen, DR6, CD30, and CD40. This family of receptors is distinguished with multiple cysteine-rich domains for ligand binding, a single transmembrane sequence, and a noncatalytic cytoplasmic domain (1). The intracellular region of the p55 tumor necrosis factor receptor, Fas receptor, and p75 contains a death domain sequence (2). The death domain serves as a proteinprotein docking site and is required for initiating tumor necrosis factor-and Fas-mediated apoptosis (3).The p75 receptor is recognized by all the neurotrophins (NGF, 3 brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4), which promote differentiation, growth, and survival of diverse cell types in the nervous system (4 -6). Neurotrophins also initiate signaling through Trk tyrosine kinase receptors, which are capable of forming high affinity binding sites with p75 to potentiate responses at low concentrations of neurotrophins (7). The precursor form of neurotrophins (proneurotrophins) binds more avidly to p75 than the mature form (8, 9). In the absence of Trk receptors, p75 is capable of independent signaling that activates NF-B, c-Jun N-terminal kinase (JNK), and the sphingomyelin cycle (10). In selected cell types, p75 can initiate cell death (11-13). Alternatively, p75 can serve as a co-receptor for several proteins that modulate axon outgrowth, such as Nogo, neuropilin-1, and plexin-A4 (14 -16). Recently, p75 interaction with ephrin A has been shown to direct targeting of retinal ganglion cells during development (17).Intramembrane cleavage events have been detected for p75 in many cell types (18,19). Proteolysis through presenilin-dependent ␥-secretase activity has emerged as a highly conserved and prevalent mechanism in receptor signaling responsible for the intramembrane c...

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Section: Discussionmentioning

confidence: 99%

Nuclear Localization of the p75 Neurotrophin Receptor Intracellular Domain

Parkhurst

Zampieri

Chao

2010

Journal of Biological Chemistry

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“…BTIC self-renewal (secondary sphere-forming) assays were performed under neural stem cell conditions as described previously (3,32). Spheres were dissociated and viable cells were counted.…”

Section: Self-renewal Assaymentioning

confidence: 99%

“…Patient-derived BTICs from newly diagnosed (BT73, BT108, BT126, BT127, BT134, BT164) and recurrent (BT119, BT143, BT147) tumors were implanted into the brain of mice as described previously (3,32,34). Mice were monitored weekly and tumor growth was assessed using the IVIS-200 Optical in vivo imaging system, MRI, or by IHC at designated timepoints.…”

Section: Characterization Of Btics In Vivomentioning

confidence: 99%

“…DSF-Cu combined with temozolomide significantly inhibited tumor growth and prolonged survival in patient-derived BTIC intracranial models As the in vitro data indicated that DSF-Cu is cytotoxic in a wide range of patient-derived BTICs and had the ability to enhance the cytotoxic effects of temozolomide in vitro, we assessed the clinical applicability of this treatment regime in our well-defined preclinical in vivo models (2,3,13,32). For these studies, we chose genetically distinct patient-derived BTICs established from a newly diagnosed (BT134: P53WT, PTENWT, EGFR WT, MGMT unmethylated), recurrent (BT147: P53mut, PTEN À/À , EGFRVIII, MGMT unmethylated), and temozolomide-resistant (BT73R) tumors.…”

Section: Dsf-cu Augments the Cytotoxic Effects Of Temozolomide And Enmentioning

confidence: 99%

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Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma

Lun

Wells

Grinshtein

et al. 2016

Clinical Cancer Research

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163

119

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Purpose: Glioblastoma is one of the most lethal cancers in humans, and with existing therapy, survival remains at 14.6 months. Current barriers to successful treatment include their infiltrative behavior, extensive tumor heterogeneity, and the presence of a stem-like population of cells, termed brain tumor-initiating cells (BTIC) that confer resistance to conventional therapies.Experimental Design: To develop therapeutic strategies that target BTICs, we focused on a repurposing approach that explored already-marketed (clinically approved) drugs for therapeutic potential against patient-derived BTICs that encompass the genetic and phenotypic heterogeneity of glioblastoma observed clinically.Results: Using a high-throughput in vitro drug screen, we found that montelukast, clioquinol, and disulfiram (DSF) were cytotoxic against a large panel of patient-derived BTICs. Of these compounds, disulfiram, an off-patent drug previously used to treat alcoholism, in the presence of a copper supplement, showed low nanomolar efficacy in BTICs including those resistant to temozolomide and the highly infiltrative quiescent stem-like population. Low dose DSF-Cu significantly augmented temozolomide activity in vitro, and importantly, prolonged in vivo survival in patient-derived BTIC models established from both newly diagnosed and recurrent tumors. Moreover, we found that in addition to acting as a potent proteasome inhibitor, DSF-Cu functionally impairs DNA repair pathways and enhances the effects of DNA alkylating agents and radiation. These observations suggest that DSF-Cu inhibits proteasome activity and augments the therapeutic effects of DNA-damaging agents (temozolomide and radiation).Conclusions: DSF-Cu should be considered as an adjuvant therapy for the treatment of patients with glioblastoma in both newly diagnosed and recurrent settings.

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“…Many molecules have been implicated in malignant glioma invasion (Salhia et al, 2006;Johnston et al, 2007;Wang et al, 2008), but the molecular mechanisms that regulate MGC invasion remain elusive. This study shows a novel functional-screening assay to identify promoters of invasion.…”

Section: Discussionmentioning

confidence: 99%

DRR drives brain cancer invasion by regulating cytoskeletal-focal adhesion dynamics

Angers-Loustau

Oliveira

et al. 2010

Oncogene

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Malignant glioma invasion is a primary cause of brain cancer treatment failure, yet the molecular mechanisms underlying its regulation remain elusive. We developed a novel functional-screening strategy and identified downregulated in renal cell carcinoma (DRR) as a regulator of invasion. We show that DRR drives invasion in vitro and in vivo. We found that while DRR is not expressed in normal glial cells, it is highly expressed in the invasive component of gliomas. Exploring underlying mechanisms, we show that DRR associates with and organizes the actin and microtubular cytoskeletons and that these associations are essential for focal adhesion (FA) disassembly and cell invasion. These findings identify DRR as a new cytoskeletal crosslinker that regulates FA dynamics and cell movement.

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Gamma-Secretase Represents a Therapeutic Target for the Treatment of Invasive Glioma Mediated by the p75 Neurotrophin Receptor

Cited by 67 publications

References 75 publications

Nuclear Localization of the p75 Neurotrophin Receptor Intracellular Domain

Nuclear Localization of the p75 Neurotrophin Receptor Intracellular Domain

Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma

DRR drives brain cancer invasion by regulating cytoskeletal-focal adhesion dynamics

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