Deciphering the signaling pathways of cancer stem cells of glioblastoma multiforme: Role of Akt/mTOR and MAPK pathways

Jhanwar‐Uniyal, Meena; Albert, Ladislau; McKenna, Elise; Karsy, Michael; Rajdev, Priya; Braun, Alex; Murali, Raj

doi:10.1016/j.advenzreg.2010.09.017

Cited by 30 publications

(25 citation statements)

References 34 publications

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“…Most investigation has focused on PI3K activity in the proliferative and migratory phenotypes of differentiated glioblastoma cells (14,25,(33)(34)(35)(36), however, little is known regarding the activity of PI3K isoforms in GBM CSC. In the present study, we examined expression and signalling of class I A PI3K isoforms in two models of GBM CSC.…”

Section: Introductionmentioning

confidence: 99%

Targeted inhibition of dominant PI3-kinase catalytic isoforms increase expression of stem cell genes in glioblastoma cancer stem cell models

Jones

Rowe

Shepherd

et al. 2016

International Journal of Oncology

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Abstract. Cancer stem cells (CSC) exhibit therapy resistance and drive self-renewal of the tumour, making cancer stem cells an important target for therapy. The PI3K signalling pathway has been the focus of considerable research effort, including in glioblastoma (GBM), a cancer that is notoriously resistant to conventional therapy. Different isoforms of the catalytic subunit have been associated with proliferation, migration and differentiation in stem cells and cancer stem cells. Blocking these processes in CSC would improve patient outcome. We examined the effect of isoform specific PI3K inhibitors in two models of GBM CSC, an established GBM stem cell line 08/04 and a neurosphere formation model. We identified the dominant catalytic PI3K isoform for each model, and inhibition of the dominant isoform blocked AKT phosphorylation, as did pan-PI3K/mTOR inhibition. Analysis of SOX2, OCT4 and MSI1 expression revealed that inhibition of the dominant p110 subunit increased expression of cancer stem cell genes, while pan-PI3K/mTOR inhibition caused a similar, though not identical, increase in cancer stem cell gene expression. This suggested that PI3K inhibition enhanced, rather than blocked, CSC activity. Careful analysis of the response to specific isoform inhibition will be necessary before specific subunit inhibitors can be successfully deployed against GBM CSC.

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Section: Introductionmentioning

confidence: 99%

Targeted inhibition of dominant PI3-kinase catalytic isoforms increase expression of stem cell genes in glioblastoma cancer stem cell models

Jones

Rowe

Shepherd

et al. 2016

International Journal of Oncology

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“…Aberrant signaling pathways contributing to abnormal cell migration, invasion, proliferation, as well as CSC maintenance are responsible for the aggressive nature of GBM (10). Many of the identified mutations result in activation of the lipid kinase PI3K and its downstream target, the plekstrin-homologydomain serine threonine kinase AKT.…”

Section: Introductionmentioning

confidence: 99%

“…AKT has over 40 downstream targets (11). Prominent among these is mechanistic target of rapamycin (mTOR; AKA mammalian target of rapamycin) and recent reports have linked PI3K/Akt/mTOR activity directly to CSC expansion and maintenance (10,12). mTOR is an atypical serine/threonine kinase that regulates several processes including autophagy, ribosome biogenesis, and metabolism by integrating signals from growth factors, nutrients, oxygen and energy status (13).…”

Section: Introductionmentioning

confidence: 99%

Targeting cancer stem cells in glioblastoma multiforme using mTOR inhibitors and the differentiating agent all-trans retinoic acid

et al. 2013

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Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, portends a poor prognosis despite current treatment modalities. Recurrence of tumor growth is attributed to the presence of treatment-resistant cancer stem cells (CSCs). The targeting of these CSCs is therefore essential in the treatment of this disease. Mechanistic target of rapamycin (mTOR) forms two multiprotein complexes, mTORC1 and mTORC2, which regulate proliferation and migration, respectively. Aberrant function of mTOR has been shown to be present in GBM CSCs. All-trans retinoic acid (ATRA), a derivative of retinol, causes differentiation of CSCs as well as normal neural progenitor cells. The purpose of this investigation was to delineate the role of mTOR in CSC maintenance, and to establish the mechanism of targeting GBM CSCs using differentiating agents along with inhibitors of the mTOR pathways. The results demonstrated that ATRA caused differentiation of CSCs, as demonstrated by the loss of the stem cell marker Nestin. These observations were confirmed by western blotting, which demonstrated a time-dependent decrease in Nestin expression following ATRA treatment. This effect occurred despite combination with mTOR (rapamycin), PI3K (LY294002) and MEK1/2 (U0126) inhibitors. Expression of activated extracellular signal-regulated kinase 1/2 (pERK1/2) was enhanced following treatment with ATRA, independent of mTOR pathway inhibitors. Proliferation of CSCs, determined by neurosphere diameter, was decreased following treatment with ATRA alone and in combination with rapamycin. The motility of GBM cells was mitigated by treatment with ATRA, rapamycin and LY29002 alone. However, combination treatment augmented the inhibitory effect on migration suggesting synergism. These findings indicate that ATRA-induced differentiation is mediated via the ERK1/2 pathway, and underscores the significance of including differentiating agents along with inhibitors of mTOR pathways in the treatment of GBM.

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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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Deciphering the signaling pathways of cancer stem cells of glioblastoma multiforme: Role of Akt/mTOR and MAPK pathways

Cited by 30 publications

References 34 publications

Targeted inhibition of dominant PI3-kinase catalytic isoforms increase expression of stem cell genes in glioblastoma cancer stem cell models

Targeted inhibition of dominant PI3-kinase catalytic isoforms increase expression of stem cell genes in glioblastoma cancer stem cell models

Targeting cancer stem cells in glioblastoma multiforme using mTOR inhibitors and the differentiating agent all-trans retinoic acid

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

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