Effect of inhibition of α-secretase activity on cleavage of p75 neurotrophin receptor (p75NTR) and proliferation of brain tumor initiating cells (BTICs) and malignant gliomas (MGs).

e13026 Background: Malignant gliomas (MGs) are resistant to Radiotherapy (RT). The molecular pathways that produce resistance to therapy and ability to tolerate hypoxia are poorly understood. We previously found that the p75NTR causes invasion & proliferation of MGs/Brain Tumor Initiating Cells (BTICs). We think MGs use the neurotrophin-rich brain environment as a survival advantage to resist treatment by expressing the p75NTR. We hypothesize that hypoxia cause p75NTR proteolysis which produces HIF-1α stabilization and activation of hypoxic responses. This repertoire of hypoxic responses leads to resistance to both hypoxia & radiotherapy (RT) and account for MG recurrence. Methods: We used glioma cells and BTICs they express very low or and high levels of p75NTR and manipulated the expression of p75NTR by shRNAs and activation by mutant receptors and pharmacological inhibitors. We exposed these cells to hypoxia and radiation treatment and performed biochemical and functional assays. We have also used paired pre and post-RT frozen patient specimens. Gene expression profiles were analyzed for patients using microarray expression data for 516 primary GBM patients from the TCGA and 239 patients from Moffitt’s Total Cancer Care (TCC) project. Results: We found that inhibiting p75NTR pharmacologically significantly reduced invasion/proliferation of MGs/BTICs in vitro & in vivo. We have also found that p75NTR is required for HIF-1α stabilization and VEGF expression in MGs/BTICs in vitro & in vivo, that p75NTR expressing MGs/BTICs are very resistant to hypoxia & RT in vitro, and these effects are reversed with inhibition of p75NTR signaling. In addition, p75NTR expression and its cleavage are associated with treatment resistance in patient specimens. We also found using TCGA and Moffitt patient specimen data that the p75NTR/Siah2/PHD axis is expressed in MG patients and associated with RT resistance/poor prognosis. Conclusions: These results suggest that p75NTR expression/cleavage are required for HIF-1α pathway activation and hence the phenotype of MGs/BTICs and their treatment resistance. Targeting the p75NTR signaling axis therefore will provide novel therapeutic approaches.

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ETS-Domain Transcription Factor Elk-1 Regulates Stemness Genes in Brain Tumors and CD133+ BrainTumor-Initiating Cells

Journal of Personalized Medicine ◽

10.3390/jpm11020125 ◽

2021 ◽

Vol 11 (2) ◽

pp. 125

Author(s):

Melis Savasan Sogut ◽

Chitra Venugopal ◽

Basak Kandemir ◽

Ugur Dag ◽

Sujeivan Mahendram ◽

...

Keyword(s):

Transcription Factor ◽

Brain Tumor ◽

Brain Tumors ◽

System Development ◽

Nervous System Development ◽

Stem Cell Population ◽

Tumor Initiating Cells ◽

Specific Domain ◽

Brain Tumor Initiating Cells ◽

Ets Domain

Elk-1, a member of the ternary complex factors (TCFs) within the ETS (E26 transformation-specific) domain superfamily, is a transcription factor implicated in neuroprotection, neurodegeneration, and brain tumor proliferation. Except for known targets, c-fos and egr-1, few targets of Elk-1 have been identified. Interestingly, SMN, SOD1, and PSEN1 promoters were shown to be regulated by Elk-1. On the other hand, Elk-1 was shown to regulate the CD133 gene, which is highly expressed in brain-tumor-initiating cells (BTICs) and used as a marker for separating this cancer stem cell population. In this study, we have carried out microarray analysis in SH-SY5Y cells overexpressing Elk-1-VP16, which has revealed a large number of genes significantly regulated by Elk-1 that function in nervous system development, embryonic development, pluripotency, apoptosis, survival, and proliferation. Among these, we have shown that genes related to pluripotency, such as Sox2, Nanog, and Oct4, were indeed regulated by Elk-1, and in the context of brain tumors, we further showed that Elk-1 overexpression in CD133+ BTIC population results in the upregulation of these genes. When Elk-1 expression is silenced, the expression of these stemness genes is decreased. We propose that Elk-1 is a transcription factor upstream of these genes, regulating the self-renewal of CD133+ BTICs.

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CS-14 * NEUROTROPHIN RECEPTORS TrkB AND TrkC ARE REQUIRED FOR SURVIVAL OF BRAIN TUMOR INITIATING CELLS

Neuro-Oncology ◽

10.1093/neuonc/nou242.14 ◽

2014 ◽

Vol 16 (suppl 5) ◽

pp. v54-v54

Author(s):

R. Kenchappa ◽

S. Lawn ◽

N. Krishna ◽

X. Qu ◽

D. Fenstermacher ◽

...

Keyword(s):

Brain Tumor ◽

Neurotrophin Receptors ◽

Tumor Initiating Cells ◽

Brain Tumor Initiating Cells

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Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1701911114 ◽

2017 ◽

Vol 114 (30) ◽

pp. E6147-E6156 ◽

Cited By ~ 53

Author(s):

Dou Yu ◽

Omar F. Khan ◽

Mario L. Suvà ◽

Biqin Dong ◽

Wojciech K. Panek ◽

...

Keyword(s):

Brain Tumor ◽

Therapeutic Potential ◽

Therapy Resistance ◽

Tumor Initiating Cells ◽

Convection Enhanced Delivery ◽

Individual Gene ◽

Brain Tumor Initiating Cells ◽

Novel Therapeutic Strategies

Brain tumor-initiating cells (BTICs) have been identified as key contributors to therapy resistance, recurrence, and progression of diffuse gliomas, particularly glioblastoma (GBM). BTICs are elusive therapeutic targets that reside across the blood–brain barrier, underscoring the urgent need to develop novel therapeutic strategies. Additionally, intratumoral heterogeneity and adaptations to therapeutic pressure by BTICs impede the discovery of effective anti-BTIC therapies and limit the efficacy of individual gene targeting. Recent discoveries in the genetic and epigenetic determinants of BTIC tumorigenesis offer novel opportunities for RNAi-mediated targeting of BTICs. Here we show that BTIC growth arrest in vitro and in vivo is accomplished via concurrent siRNA knockdown of four transcription factors (SOX2, OLIG2, SALL2, and POU3F2) that drive the proneural BTIC phenotype delivered by multiplexed siRNA encapsulation in the lipopolymeric nanoparticle 7C1. Importantly, we demonstrate that 7C1 nano-encapsulation of multiplexed RNAi is a viable BTIC-targeting strategy when delivered directly in vivo in an established mouse brain tumor. Therapeutic potential was most evident via a convection-enhanced delivery method, which shows significant extension of median survival in two patient-derived BTIC xenograft mouse models of GBM. Our study suggests that there is potential advantage in multiplexed targeting strategies for BTICs and establishes a flexible nonviral gene therapy platform with the capacity to channel multiplexed RNAi schemes to address the challenges posed by tumor heterogeneity.

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Microglia induces Gas1 expression in human brain tumor-initiating cells to reduce tumorigenecity

Scientific Reports ◽

10.1038/s41598-018-33306-0 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 4

Author(s):

Susobhan Sarkar ◽

Candice C. Poon ◽

Reza Mirzaei ◽

Khalil S. Rawji ◽

Walter Hader ◽

...

Keyword(s):

Brain Tumor ◽

Human Brain ◽

Tumor Initiating Cells ◽

Human Brain Tumor ◽

Brain Tumor Initiating Cells

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The pro-tumorigenic effects of metabolic alterations in glioblastoma including brain tumor initiating cells

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer ◽

10.1016/j.bbcan.2018.01.004 ◽

2018 ◽

Vol 1869 (2) ◽

pp. 175-188 ◽

Cited By ~ 32

Author(s):

Catherine J. Libby ◽

Anh Nhat Tran ◽

Sarah E. Scott ◽

Corinne Griguer ◽

Anita B. Hjelmeland

Keyword(s):

Brain Tumor ◽

Tumor Initiating Cells ◽

Metabolic Alterations ◽

Brain Tumor Initiating Cells

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Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1712363115 ◽

2018 ◽

Vol 115 (22) ◽

pp. E5086-E5095 ◽

Cited By ~ 33

Author(s):

Liang Xu ◽

Ye Chen ◽

Anand Mayakonda ◽

Lynnette Koh ◽

Yuk Kien Chong ◽

...

Keyword(s):

Brain Tumor ◽

Acquired Resistance ◽

Transcriptional Network ◽

Next Generation ◽

Transcriptional Program ◽

Tumor Initiating Cells ◽

Self Renewal ◽

Brain Tumor Initiating Cells ◽

Bet Protein

Competitive BET bromodomain inhibitors (BBIs) targeting BET proteins (BRD2, BRD3, BRD4, and BRDT) show promising preclinical activities against brain cancers. However, the BET protein-dependent glioblastoma (GBM)-promoting transcriptional network remains elusive. Here, with mechanistic exploration of a next-generation chemical degrader of BET proteins (dBET6), we reveal a profound and consistent impact of BET proteins on E2F1- dependent transcriptional program in both differentiated GBM cells and brain tumor-initiating cells. dBET6 treatment drastically reduces BET protein genomic occupancy, RNA-Pol2 activity, and permissive chromatin marks. Subsequently, dBET6 represses the proliferation, self-renewal, and tumorigenic ability of GBM cells. Moreover, dBET6-induced degradation of BET proteins exerts superior antiproliferation effects compared to conventional BBIs and overcomes both intrinsic and acquired resistance to BBIs in GBM cells. Our study reveals crucial functions of BET proteins and provides the rationale and therapeutic merits of targeted degradation of BET proteins in GBM.

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