Deconstructing mTOR complexes in regulation of Glioblastoma Multiforme and its stem cells

Jhanwar‐Uniyal, Meena; Jeevan, Dhruve; Neil, Jayson A.; Shannon, Craig; Albert, Ladislau; Murali, Raj

doi:10.1016/j.jbior.2012.10.001

Cited by 51 publications

(48 citation statements)

References 63 publications

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“…Approaches to target PI3K [54][55][56], PTEN [57,107], Akt [58], mTOR [59,108,109], GSK-3 [60,61,110], and Raf/MEK/ERK [111][112][113] as well as apoptotic and cytokine-mediated signaling pathways [63] which often result in Jak/STAT pathway activation are being developed [64]. In addition, novel methods to inhibit NF-kappaB expression are under investigation [114][115][116][117].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Roles of NGAL and MMP-9 in the tumor microenvironment and sensitivity to targeted therapy

Candido

Abrams

Steelman

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Various, diverse molecules contribute to the tumor microenvironment and influence invasion and metastasis. In this review, the roles of neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9) in the tumor microenvironment and sensitivity to therapy will be discussed. The lipocalin family of proteins has many important functions. For example when NGAL forms a complex with MMP-9 it increases its stability which is important in cancer metastasis. Small hydrophobic molecules are bound by NGAL which can alter their entry into and efflux from cells. Iron transport and storage are also influenced by NGAL activity. Regulation of iron levels is important for survival in the tumor microenvironment as well as metastasis. Innate immunity is also regulated by NGAL as it can have bacteriostatic properties. NGAL and MMP-9 expression may also affect the sensitivity of cancer cells to chemotherapy as well as targeted therapy. Thus NGAL and MMP-9 play important roles in key processes involved in metastasis as well as response to therapy. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.

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Section: Accepted Manuscriptmentioning

confidence: 99%

Roles of NGAL and MMP-9 in the tumor microenvironment and sensitivity to targeted therapy

Candido

Abrams

Steelman

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…For example, activation of p70 S6K by mTORC1 causes feedback inhibition of IGF-1/insulin signaling by phosphorylating IRS-1 (insulin receptor substrate 1), causing IRS-1 degradation, and leads to decreased PI3K signaling and reduced AKT T308 phosphorylation. However, rapalogue-induced inhibition of mTORC1 consequently inhibits p70S6K phosphorylation, reciprocally activating negative feedback loops but relieves this feedback and induces AKT T308 re-phosphorylation, and thus increases mTORC2 activation (30,(42)(43)(44)(45). In addition, resistance to chemotherapy, and hypersensitivity to the mTORC1 inhibitor, rapamycin, in tumors with low expression of the tumor suppressor gene PTEN (reviewed in ref.…”

Section: Discussionmentioning

confidence: 99%

ATP-site binding inhibitor effectively targets mTORC1 and mTORC2 complexes in glioblastoma

Neil

Shannon

Mohan

et al. 2015

International Journal of Oncology

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Abstract. The PI3K-AKT-mTOR signaling axis is central to the transformed phenotype of glioblastoma (GBM) cells, due to frequent loss of tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10). The mechanistic target of rapamycin (mTOR) kinase is present in two cellular multi-protein complexes, mTORC1 and mTORC2, which have distinct subunit composition, substrates and mechanisms of action. Targeting the mTOR protein is a promising strategy for GBM therapy. However, neither of these complexes is fully inhibited by the allosteric inhibitor of mTOR, rapamycin or its analogs. Herein, we provide evidence that the combined inhibition of mTORC1/2, using the ATP-competitive binding inhibitor PP242, would effectively suppress GBM growth and dissemination as compared to an allosteric binding inhibitor of mTOR. GBM cells treated with PP242 demonstrated significantly decreased activation of mTORC1 and mTORC2, as shown by reduced phosphorylation of their substrate levels, p70 S6K Thr389 and AKT Ser473, respectively, in a dosedependent manner. Furthermore, insulin induced activation of these kinases was abrogated by pretreatment with PP242 as compared with rapamycin. Unlike rapamycin, PP242 modestly activates extracellular regulated kinase (ERK1/2), as shown by expression of pERK Thr202/Tyr204 . Cell proliferation and S-phase entry of GBM cells was significantly suppressed by PP242, which was more pronounced compared to rapamycin treatment. Lastly, PP242 significantly suppressed the migration of GBM cells, which was associated with a change in cellular behavior rather than cytoskeleton loss. In conclusion, these results underscore the potential therapeutic use of the PP242, a novel ATP-competitive binding inhibitor of mTORC1/2 kinase, in suppression of GBM growth and dissemination.

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“…Hyperactivation of mTOR signaling in cancers occurs via multiple mechanisms (6) and results in an increase in cell growth, causing some cell types to enter the cell cycle. Aberrant mTOR pathway activity is prevalent in glioblastoma, leading to abnormalities in cell proliferation and motility, thereby resulting in uncontrolled growth and dissemination (7,8). Mutations of PTEN are found in approximately 70-90% of glioblastoma that leads to deregulation of the PI3K/Akt/mTOR signaling axis.…”

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confidence: 99%

“…Specifically, this trial establishes the limited therapeutic effectiveness of mTOR inhibition with rapamycin and its analogs due to loss of negative feedback. Therefore, despite significant advancement in targeted therapy, glioblastoma remains incurable possibly in part due to activation of mitogenic pathways such as RAS/ERK1/2 (7,8). Preclinical and clinical studies of ATP-competitive mTOR inhibitors that target both mTORC1 and mTORC2 demonstrated greater effectiveness than rapalogs in treatment of cancer.…”

mentioning

confidence: 99%

“…Preclinical and clinical studies of ATP-competitive mTOR inhibitors that target both mTORC1 and mTORC2 demonstrated greater effectiveness than rapalogs in treatment of cancer. However, it is important to consider that the acute mTORC1 inhibition can activate the negative feedback loop leading to triggering of PI3K/PDK1/Akt (Thr308) and IRS1 via mitogenic pathways, leading to relentless cell survival and proliferation (7,8).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Mighty RapaLink-1 vanquishes undruggable mutant mTOR in glioblastoma

Jhanwar‐Uniyal¹

2017

Transl. Cancer Res

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Deconstructing mTOR complexes in regulation of Glioblastoma Multiforme and its stem cells

Cited by 51 publications

References 63 publications

Roles of NGAL and MMP-9 in the tumor microenvironment and sensitivity to targeted therapy

Roles of NGAL and MMP-9 in the tumor microenvironment and sensitivity to targeted therapy

ATP-site binding inhibitor effectively targets mTORC1 and mTORC2 complexes in glioblastoma

Mighty RapaLink-1 vanquishes undruggable mutant mTOR in glioblastoma

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