Tight regulation between cell survival and programmed cell death in GBM stem-like cells by EGFR/GSK3b/PP2A signaling

Gursel, Demirkan; Banu, Matei; Berry, Nicholas A.; Marongiu, Roberta; Burkhardt, Jan Karl; Kobylarz, Keith; Kaplitt, Michael G.; Rafii, Shahin; Boockvar, John A.

doi:10.1007/s11060-014-1602-3

Cited by 24 publications

(17 citation statements)

References 41 publications

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“…Palmitate significantly reduced the pPP2A/PP2A ratio compared to control (p = 0.04, Student's t-test) ( Figure 5(c)) suggesting increased dephosphorylation of pACC and, as a result, increased ACC activity. PP2A is also involved in the activation of the metabolic regulator GSK3β by dephosphorylating it [36]. Therefore, we measured GSK3β levels following palmitate treatment.…”

Section: Palmitate Disrupts Catabolic Pathwaysmentioning

confidence: 99%

Non-obesogenic doses of palmitate disrupt circadian metabolism in adipocytes

2019

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Saturated fatty acids, such as palmitate, lead to circadian disruption. We aimed at studying the effect of low doses of palmitate on circadian metabolism and to decipher the mechanism by which fatty acids convey their effect in adipocytes. Mice were fed non-obesogenic doses of palm or olive oil and adipocytes were treated with palmitate and oleate. Cultured adipocytes treated with oleate showed increased AMPK activity and induced the expression of mitochondrial genes indicating increased fatty acid oxidation, while palmitate increased ACC activity and induced the expression of lipogenic genes, indicating increased fatty acid synthesis. Low doses of palmitate were sufficient to alter circadian rhythms, due to changes in the expression and/or activity of key metabolic proteins including GSK3β and AKT. Palmitate-induced AKT and GSK3β activation led to the phosphorylation of BMAL1 that resulted in low levels as well as high amplitude of circadian clock expression. In adipocytes, the detrimental metabolic alteration of palmitate manifests itself early on even at non-obesogenic levels. This is accompanied by modulating BMAL1 expression and phosphorylation levels, which lead to dampened clock gene expression.

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Section: Palmitate Disrupts Catabolic Pathwaysmentioning

confidence: 99%

Non-obesogenic doses of palmitate disrupt circadian metabolism in adipocytes

2019

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“…Moreover, GSK3β phosphorylates c-MYC, a transcription factor implicated in the regulation of cell growth and proliferation [47]. Recent study suggests that GSK3β activity plays an important role in the regulation of GSCs survival and apoptosis [48]. …”

Section: Gsk3β Pathways In Gbmmentioning

confidence: 99%

AKT/GSK3β Signaling in Glioblastoma

Majewska

Szeliga

2016

Neurochem Res

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Glioblastoma (GBM) is the most aggressive of primary brain tumors. Despite the progress in understanding the biology of the pathogenesis of glioma made during the past decade, the clinical outcome of patients with GBM remains still poor. Deregulation of many signaling pathways involved in growth, survival, migration and resistance to treatment has been implicated in pathogenesis of GBM. One of these pathways is phosphatidylinositol-3 kinases (PI3K)/protein kinase B (AKT)/rapamycin-sensitive mTOR-complex (mTOR) pathway, intensively studied and widely described so far. Much less attention has been paid to the role of glycogen synthase kinase 3 β (GSK3β), a target of AKT. In this review we focus on the function of AKT/GSK3β signaling in GBM.

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“…GSK-3β can be inactivated by various signaling mechanisms, including the PI3K/AKT (Cross, Alessi, Cohen, Andjelkovich, & Hemmings, 1995), and ERK1/2 pathway (Ding et al, 2005). In glioblastoma stem-like cells, knocking down PP2A, or blocking its activity by okadaic acid inactivated GSK-3β by increasing GSK-3β phosphorylation at Serine 9 (Gursel et al, 2015). There is no available information supporting a direct association between these two signaling molecules in OSCC patients.…”

Section: Discussionmentioning

confidence: 99%

PP2A deactivation is a common event in oral cancer and reactivation by FTY720 shows promising therapeutic potential

Velmurugan

Lee²,

Chiang

et al. 2017

Journal Cellular Physiology

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Protein phosphatase 2A (PP2A) is a tumor suppressor gene, that has been frequently deactivated in many types of cancer. However, its molecular and clinical relevance in oral squamous cell carcinoma (OSCC) remain unclear. Here we show that, PP2A deactivation is a common event in oral cancer cells and hyperphosphorylation in its tyrosine-307 (Y307) residue contributes to PP2A deactivation. PP2A restoration by FTY720 treatment reduced cell growth and decreased GSK-3β phosphorylation without significantly altering other PP2A targets. We further detected PP2A phosphorylation in 262 OSCC tissues. Increased expression of p-PP2A in the tumor tissues was significantly correlated with higher N2/N3-stage (aOR = 2.1, 95%CI: 1.2-3.8). Patients with high p-PP2A expression had lower overall survival rates than those with low expression. Hazard ratio analysis showed that, high p-PP2A expression was significantly associated with mortality density (aOR = 2.2, 95%CI: 1.2-4.0) and lower 10-year overall survival (p = 0.027) in lymph node metastasis. However, no interaction was observed between p-PP2A expression and lymph node metastasis. All our results suggest that PP2A is frequently deactivated in oral cancer and determines poor outcome, restoring its expression by FTY720 can be an alternative therapeutic approach in OSCC.

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Tight regulation between cell survival and programmed cell death in GBM stem-like cells by EGFR/GSK3b/PP2A signaling

Cited by 24 publications

References 41 publications

Non-obesogenic doses of palmitate disrupt circadian metabolism in adipocytes

Non-obesogenic doses of palmitate disrupt circadian metabolism in adipocytes

AKT/GSK3β Signaling in Glioblastoma

PP2A deactivation is a common event in oral cancer and reactivation by FTY720 shows promising therapeutic potential

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