Distinct signaling mechanisms of mTORC1 and mTORC2 in glioblastoma multiforme: A tale of two complexes

Jhanwar‐Uniyal, Meena; Gillick, John L.; Neil, Jayson A.; Tobias, Michael; Thwing, Zachary E.; Murali, Raj

doi:10.1016/j.jbior.2014.09.004

Cited by 62 publications

(50 citation statements)

References 58 publications

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“…Another possible explanation is the inhibition of a negative feedback loop. Similar effects have been observed for treatment with everolimus, which inhibits the negative feedback loop on AKT through mTORC1, but not the positive feedback loop of mTORC2 and thus leads to hyperactivation of AKT (35). Together with the data of others, our findings clearly identify the AKT pathway as one major downstream mechanism being inhibited by NK1R antagonism.…”

Section: Discussionsupporting

confidence: 87%

Targeting the Neurokinin-1 Receptor Compromises Canonical Wnt Signaling in Hepatoblastoma

Ilmer

Garnier

Vykoukal

et al. 2015

Molecular Cancer Therapeutics

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The substance P (SP)/NK-1 receptor (NK1R) complex represents an intriguing anticancer target for a variety of tumors, including hepatoblastoma (HB). Therefore, NK1R antagonists, such as the clinical drug aprepitant, recently have been proposed as potent anticancer agents. However, very little is known regarding the molecular basis of NK1R inhibition in cancer. Using reverse phase protein array, Western blot, Super TOP/FOP, confocal microscopy, and sphere formation ability (SFA) assays, we identified the AKT and Wnt signaling pathways as the key targets of aprepitant in three human HB cell lines (HepT1, HepG2, and HuH6). Following NK1R blockage, we observed decreased phosphorylation of p70S6K and 4E-BP1/2 and inhibition of the canonical Wnt pathway with subsequent decrease of HB cell growth. This effect was dependent of high baseline Wnt activity either by mutational status of b-catenin or extrinsic Wnt activation. Wnt inhibition seemed to be strengthened by disruption of the FOXM1-b-catenin complex. Furthermore, treatment of HB cells with aprepitant led to reduced expression of (liver) stemness markers (AFP, CD13, SOX2, NANOG, and OCT4) and SFA when grown under cancer stem cell conditions. Taken together, we show for the first time that targeting the SP/NK1R signaling cascade inhibits canonical Wnt signaling in HB cells. These findings reveal important insight into the molecular mechanisms of the SP/NK1R complex as a critical component in a model of pediatric liver cancer and may support the development of novel therapeutic interventions for HB and other Wnt-activated cancers.

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Section: Discussionsupporting

confidence: 87%

Targeting the Neurokinin-1 Receptor Compromises Canonical Wnt Signaling in Hepatoblastoma

Ilmer

Garnier

Vykoukal

et al. 2015

Molecular Cancer Therapeutics

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“…In NCT01430351, metformin was combined with TMZ. Both of the trials are still in phase I state.geting specifically mTORC2 could thereby be a better approach, since it would directly block Akt phosphorylation without perturbing the mTORC1-dependent feedback loops [78, 79]. In contrast to mTORC1, mTORC1/2 inhibitors can restrain Akt phosphorylation at Ser473, thus also inhibit mTORC2 at the same time [63].…”

Section: The Development Of Targeted Therapy Towards Egfr and Pi3k/akmentioning

confidence: 99%

PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma

et al. 2016

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Glioblastoma multiform (GBM) is the most common malignant glioma of all the brain tumors and currently effective treatment options are still lacking. GBM is frequently accompanied with overexpression and/or mutation of epidermal growth factor receptor (EGFR), which subsequently leads to activation of many downstream signal pathways such as phosphatidylinositol 3-kinase (PI3K)/Akt/rapamycin-sensitive mTOR-complex (mTOR) pathway. Here we explored the reason why inhibition of the pathway may serve as a compelling therapeutic target for the disease, and provided an update data of EFGR and PI3K/Akt/mTOR inhibitors in clinical trials.

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“…RUNX1 OE led to direct down-regulation of the expression of numerous genes in key pathways in GBM development such as EMT, MTORC1, hypoxia, and TNFa. [53][54][55][56] Of note, genes that were up-regulated upon RUNX1 OE did not significantly correspond to any known transcriptional pathways or expression signatures. Moreover, the specificity of the RUNX1 effect when overexpressed was further corroborated by the minute transcriptional response following RUNX1 silencing.…”

Section: Discussionmentioning

confidence: 99%

Augmented expression of RUNX1 deregulates the global gene expression of U87 glioblastoma multiforme cells and inhibits tumor growth in mice

et al. 2017

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Glioblastoma multiforme is the most common and aggressive primary brain tumor in adults. A mesenchymal phenotype was associated with tumor aggressiveness and poor prognosis in glioblastoma multiforme patients. Recently, the transcription factor RUNX1 was suggested as a driver of the glioblastoma multiforme mesenchymal gene expression signature; however, its independent role in this process is yet to be described. Here, we assessed the role of RUNX1 in U87 glioblastoma multiforme cells in correspondence to its mediated transcriptome and genome-wide occupancy pattern. Overexpression of RUNX1 led to diminished tumor growth in nude and severe combined immunodeficiency mouse xenograft tumor model. At the molecular level, RUNX1 occupied thousands of genomic regions and regulated the expression of hundreds of target genes, both directly and indirectly. RUNX1 occupied genomic regions that corresponded to genes that were shown to play a role in brain tumor progression and angiogenesis and upon overexpression led to a substantial down-regulation of their expression level. When overexpressed in U87 glioblastoma multiforme cells, RUNX1 down-regulated key pathways in glioblastoma multiforme progression including epithelial to mesenchymal transition, MTORC1 signaling, hypoxia-induced signaling, and TNFa signaling via NFkB. Moreover, master regulators of the glioblastoma multiforme mesenchymal phenotype including CEBPb, ZNF238, and FOSL2 were directly regulated by RUNX1. The data suggest a central role for RUNX1 as master regulator of gene expression in the U87 glioblastoma multiforme cell line and mark RUNX1 as a potential target for novel future therapies for glioblastoma multiforme.

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Distinct signaling mechanisms of mTORC1 and mTORC2 in glioblastoma multiforme: A tale of two complexes

Cited by 62 publications

References 58 publications

Targeting the Neurokinin-1 Receptor Compromises Canonical Wnt Signaling in Hepatoblastoma

Targeting the Neurokinin-1 Receptor Compromises Canonical Wnt Signaling in Hepatoblastoma

PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma

Augmented expression of RUNX1 deregulates the global gene expression of U87 glioblastoma multiforme cells and inhibits tumor growth in mice

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