A molecular cascade modulates MAP1B and confers resistance to mTOR inhibition in human glioblastoma

Laks, Dan R.; Oses-Prieto, Juan; Alvarado, Alvaro G.; Nakashima, Jonathan; Chand, Shreya; Azzam, Daniel; Gholkar, Ankur A.; Sperry, Jantzen; Ludwig, Kirsten; Condro, Michael C.; Nazarian, Serli; Cardenas, Anjelica; Shih, Michelle Y. S.; Damoiseaux, Robert; Orozco, Nicholas; Visnyei, Koppany; Crisman, Thomas J.; Gao, Fuying; Torres, Jorge Z.; Coppola, Giovanni; Burlingame, Alma L.; Kornblum, Harley I.

doi:10.1093/neuonc/nox215

Cited by 25 publications

(26 citation statements)

References 45 publications

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“…Moreover, depletion of GSK3β through shRNA strategy resulted in a marked enhancement of resistance to NVP-BEZ235. In contrast, knockdown of GSK3α had no effects on drug-resistance [108]. Interestingly, Rictor (an mTORC2 component [90]) knockdown by shRNA prevented the development of resistance to NVP-BEZ235, thereby suggesting the involvement of mTORC2.…”

Section: Gsk3 Involvement In Resistance To Dual Pi3k/mtor Inhibitorsmentioning

confidence: 95%

“…The involvement of GSK3β in the resistance to the dual PI3K/mTOR inhibitor, NVP-BEZ235, has been documented in human primary GBM cells chronically exposed to this drug [108]. It is worth pointing out that PI3K/Akt/mTOR signaling is frequently altered in GBM [109], however mTOR-targeted therapeutics have failed to improve patient outcome [110].…”

Section: Gsk3 Involvement In Resistance To Dual Pi3k/mtor Inhibitorsmentioning

confidence: 99%

“…Laks and coworkers [108] were also able to identify microtubuleassociated protein (MAP)1B, as a downstream target of MEK/ERK/ p90RSK/GSK3β signaling that led to the development of acquired resistance to NVP-BEZ235 in human GBM cells. Indeed, either GSK3β pharmacological inhibition or depletion of GSK3β via shRNA strategy, decreased the levels of p-MAP1B, a GSK3β substrate.…”

Section: Gsk3 Involvement In Resistance To Dual Pi3k/mtor Inhibitorsmentioning

confidence: 99%

“…Indeed, either GSK3β pharmacological inhibition or depletion of GSK3β via shRNA strategy, decreased the levels of p-MAP1B, a GSK3β substrate. However, GSK3βdependent phosphorylation had been previously mapped to the Ser1260 and Thr1265 residues of MAP1B [116], while Laks and et al [108] identified Thr1270 as the hyperphosphorylated residue. Therefore, it could be hypothesized that the enhanced phosphorylation of MAP1B could be due either to the upregulation of a protein kinase or the downregulation of a protein phosphatase that both are controlled via the MEK/ERK/p90RSK/GSK3β axis.…”

Section: Gsk3 Involvement In Resistance To Dual Pi3k/mtor Inhibitorsmentioning

confidence: 99%

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Crosstalks of GSK3 signaling with the mTOR network and effects on targeted therapy of cancer

Evangelisti

Chiarini

Paganelli

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Section: Gsk3 Involvement In Resistance To Dual Pi3k/mtor Inhibitorsmentioning

confidence: 95%

Section: Gsk3 Involvement In Resistance To Dual Pi3k/mtor Inhibitorsmentioning

confidence: 99%

Section: Gsk3 Involvement In Resistance To Dual Pi3k/mtor Inhibitorsmentioning

confidence: 99%

Section: Gsk3 Involvement In Resistance To Dual Pi3k/mtor Inhibitorsmentioning

confidence: 99%

See 2 more Smart Citations

Crosstalks of GSK3 signaling with the mTOR network and effects on targeted therapy of cancer

Evangelisti

Chiarini

Paganelli

et al. 2020

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…Since most of these variants occur in cNF samples but not in the other tumor types, it is not surprising that this latent variable is down-regulated across all cNFs ( Figure 4C). Figure 4D shows that MAP1B, which has been reported to play a role in glioblastoma [51] but has not been studied in NF1-linked tumors, is a major contributor towards this LV.…”

Section: Scores May Be Attributed To Specific Gene Variants For Spmentioning

confidence: 98%

Integrative analysis identifies candidate tumor microenvironment and intracellular signaling pathways that define tumor heterogeneity in NF1

Banerjee

Allaway

Taroni

et al. 2020

Preprint

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Neurofibromatosis type 1 is a monogenic syndrome that gives rise to numerous symptoms including cognitive impairment, skeletal abnormalities, and growth of benign nerve sheath tumors. Nearly all NF1 patients develop cutaneous neurofibromas (cNFs), which occur on the skin surface, while 40-60% of patients develop plexiform neurofibromas (pNFs) which are deeply embedded in the peripheral nerves. Patients with pNFs have a ~10% lifetime chance of these tumors becoming malignant peripheral nerve sheath tumors (MPNSTs). These tumors have a severe prognosis and few treatment options other than surgery. Given the lack of therapeutic options available to patients with these tumors, identification of druggable pathways or other key molecular features could aid ongoing therapeutic discovery studies. In this work, we used statistical and machine learning methods to analyze 77 NF1 tumors with genomic data to characterize key signaling pathways that distinguish these tumors and identify candidates for drug development. We identified subsets of latent gene expression variables that may be important in the identification and etiology of cNFs, pNFs, other neurofibromas, and MPNSTs. Furthermore, we characterized the association between these latent variables and genetic variants, immune deconvolution predictions, and protein activity predictions.

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Protein phosphorylation: A potential target in glioma development

Fang

2022

Ibrain

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Glioma is one of the most common primary brain tumors, and mortality due to this disease is second only to cardiovascular and cerebrovascular diseases. In traditional surgery, it is difficult to eradicate glioma; often recurrence increases its malignant degree, leading to a large number of patients killed by this disease. It is one of the most important subjects to study its pathogenesis and explore effective treatment methods. Research on glioma mechanisms mainly focuses on the effect of DNA methylation in epigenetics. Although there are many studies on protein phosphorylation, there is no overall regulatory mechanism. Protein phosphorylation regulates a variety of cell functions, such as cell growth, division and differentiation, and apoptosis. As a consequence, protein phosphorylation plays a leading part in various activities of glioma, and can also be used as a target to regulate the development of glioma. This review is aimed at studying the effect of protein phosphorylation on glioma, understanding the pathological mechanism, and an in‐depth analysis of it. The following is a discussion on glioma growth, migration and invasion, resistance and death in phosphorylation, and the possibility of treating glioma by phosphorylation.

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A molecular cascade modulates MAP1B and confers resistance to mTOR inhibition in human glioblastoma

Cited by 25 publications

References 45 publications

Crosstalks of GSK3 signaling with the mTOR network and effects on targeted therapy of cancer

Crosstalks of GSK3 signaling with the mTOR network and effects on targeted therapy of cancer

Integrative analysis identifies candidate tumor microenvironment and intracellular signaling pathways that define tumor heterogeneity in NF1

Protein phosphorylation: A potential target in glioma development

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