The p75 Neurotrophin Receptor Is a Central Regulator of Glioma Invasion

Johnston, Angela L. M; Lun, Xueqing; Rahn, Jennifer J.; Liacini, Abdelhamid; Wang, Limei; Hamilton, Mark G.; Parney, Ian F.; Hempstead, Barbara L.; Robbins, Stephen M.; Forsyth, Peter; Senger, Donna L.

doi:10.1371/journal.pbio.0050212

Cited by 160 publications

(180 citation statements)

References 69 publications

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“…Equal protein amounts were subjected to SDS-PAGE, transferred to nitrocellulose, and Western blot analysis was performed as described previously (33,34) using the appropriate primary and secondary antibodies.…”

Section: Western Blot Analysismentioning

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%

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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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164

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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Section: Western Blot Analysismentioning

confidence: 99%

Section: Characterization Of Btics In Vivomentioning

confidence: 99%

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

Self Cite

164

119

View full text Add to dashboard Cite

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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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“…These results are of particular interest, since EGFR is known to be expressed in GNPCs of the human cerebellum, participating in its normal development and function (Seroogy et al, 1995). Recently, the multifunctional signaling protein neurotrophin receptor p75 NTR was shown to be a central regulator for GBM (Johnston et al, 2007) and MB spinal invasion while -secretase inhibitor, which blocks p75 NTR proteolytic processing, significantly abrogates p75 NTR induced MB migration and invasion in vitro and in vivo (Wang et al, 2010). The transwell assays, even though used commonly for cell migration experiments, often yield inconsistent results across research groups due to the experimental individual assay modifications made by each group.…”

Section: Transwell Migration Assaysmentioning

confidence: 99%