Mutant epidermal growth factor receptor displays increased signaling through the phosphatidylinositol-3 kinase/AKT pathway and promotes radioresistance in cells of astrocytic origin

Li, Bin; Yuan, Min; Kim, In-Ah; Chang, Chi-Ming; Bernhard, Eric J.; Shu, Hui

doi:10.1038/sj.onc.1207602

Cited by 158 publications

(127 citation statements)

References 26 publications

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“…We determined EGFRvIII status by immunohistochemistry using the well-defined antibody DH8.3 and verified our results at the RNA level by RT -PCR on a subset of 45 tumours showing positive immunostaining for EGFR or downstream targets. As EGFRvIII heterodimerises with wtEGFR, is constitutively phosphorylated and activates AKT and to a lesser extent ERK, we hypothesised that the chance of finding EGFRvIII-positive tumours was largest in this subgroup (Montgomery et al, 1995;Li et al, 2004;Luwor et al, 2004). As we did not detect any EGFRvIII positivity in this subgroup, nor in 10 tumours that did not overexpress any of the studied markers, our data strongly suggest that EGFRvIII signalling does not play a major role in ovarian cancer.…”

Section: Discussionmentioning

confidence: 48%

The ErbB signalling pathway: protein expression and prognostic value in epithelial ovarian cancer

et al. 2008

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Ovarian cancer is the most frequent cause of death from gynaecological cancer in the Western world. Current prognostic factors do not allow reliable prediction of response to chemotherapy and survival for individual ovarian cancer patients. Epidermal growth factor receptor (EGFR) and HER-2/neu are frequently expressed in ovarian cancer but their prognostic value remains unclear. In this study, we investigated the expression and prognostic value of EGFR, EGFR variant III (EGFRvIII), HER-2/neu and important downstream signalling components in a large series of epithelial ovarian cancer patients. Immunohistochemical staining of EGFR, pEGFR, EGFRvIII, Her-2/neu, PTEN (phosphatase and tensin homologue deleted on chromosome 10), total and phosphorylated AKT (pAKT) and phosphorylated ERK (pERK) was performed in 232 primary tumours using the tissue microarray platform and related to clinicopathological characteristics and survival. In addition, EGFRvIII expression was determined in 45 tumours by RT -PCR. Our results show that negative PTEN immunostaining was associated with stage I/II disease (P ¼ 0.006), non-serous tumour type (P ¼ 0.042) and in multivariate analysis with a longer progression-free survival (P ¼ 0.015). Negative PTEN staining also predicted improved progression-free survival in patients with grade III or undifferentiated serous carcinomas (P ¼ 0.011). Positive pAKT staining was associated with advanced-stage disease (P ¼ 0.006). Other proteins were expressed only at low levels, and were not associated with any clinicopathological parameter or survival. None of the tumours were positive for EGFRvIII. In conclusion, our results indicate that tumours showing negative PTEN staining could represent a subgroup of ovarian carcinomas with a relatively favourable prognosis.

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Section: Discussionmentioning

confidence: 48%

The ErbB signalling pathway: protein expression and prognostic value in epithelial ovarian cancer

et al. 2008

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“…We next asked whether there was an effect on nontransformed cells. These experiments were done using an immortalized normal human astrocyte line (NHA) that has been described previously (36,37). Pretreatment of these cells with LY294002 blunted the hypoxic induction of HIF-1a (Fig.…”

Section: Resultsmentioning

confidence: 99%

Akt1 Activation Can Augment Hypoxia-Inducible Factor-1α Expression by Increasing Protein Translation through a Mammalian Target of Rapamycin–Independent Pathway

Pore

Jiang

Shu

et al. 2006

Molecular Cancer Research

172

134

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The phosphoinositide 3-kinase (PI3K)/Akt pathway is commonly activated in cancer; therefore, we investigated its role in hypoxia-inducible factor-1A (HIF-1A) regulation. Inhibition of PI3K in U87MG glioblastoma cells, which have activated PI3K/Akt activity secondary to phosphatase and tensin homologue deleted on chromosome 10 (PTEN) mutation, with LY294002 blunted the induction of HIF-1A protein and its targets vascular endothelial growth factor and glut1 mRNA in response to hypoxia. Introduction of wild-type PTEN into these cells also blunted HIF-1A induction in response to hypoxia and decreased HIF-1A accumulation in the presence of the proteasomal inhibitor MG132. Akt small interfering RNA (siRNA) also decreased HIF-1A induction under hypoxia and its accumulation in normoxia in the presence of dimethyloxallyl glycine, a prolyl hydroxylase inhibitor that prevents HIF-1A degradation. Metabolic labeling studies showed that Akt siRNA decreased HIF-1A translation in normoxia in the presence of dimethyloxallyl glycine and in hypoxia. Inhibition of mammalian target of rapamycin (mTOR) with rapamycin (10-100 nmol/L) had no significant effect on HIF-1A induction in a variety of cell lines, a finding that was confirmed using mTOR siRNA. Furthermore, neither mTOR siRNA nor rapamycin decreased HIF-1A translation as determined by metabolic labeling studies. Therefore, our results indicate that Akt can augment HIF-1A expression by increasing its translation under both normoxic and hypoxic conditions; however, the pathway we are investigating seems to be rapamycin insensitive and mTOR independent. These observations, which were made on cells grown in standard tissue culture medium (10% serum), were confirmed in PC3 prostate carcinoma cells. We did find that rapamycin could decrease HIF-1A expression when cells were cultured in low serum, but this seems to represent a different pathway. (Mol Cancer Res 2006;4(7):471 -9)

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“…Astrocyte differentiation from neural stem cells is controlled by Akt signaling through STAT3, N-CoR, or p27 deregulation (24-26), whereas Akt/mTOR hyperactivation is observed in reactive astrocytes responding to spinal cord injury (27). Similarly, Akt drives astrocyte survival and proliferation initiated by RTK activation (28,29). The importance of Akt/mTOR signaling to astrocyte proliferation is also underscored by glioma-associated tumor mutations, including the PTEN, TSC, and NF1 tumor suppressor genes.…”

Section: Discussionmentioning

confidence: 99%

Neurofibromatosis-1 regulates mTOR-mediated astrocyte growth and glioma formation in a TSC/Rheb-independent manner

Banerjee

Crouse

Emnett

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Converging evidence from the analysis of human brain tumors and genetically engineered mice has revealed that the mammalian target of rapamycin (mTOR) pathway is a central regulator of glial and glioma cell growth. In this regard, mutational inactivation of neurofibromatosis-1 (NF1), tuberous sclerosis complex (TSC), and PTEN genes is associated with glioma formation, such that pharmacologic inhibition of mTOR signaling results in attenuated tumor growth. This shared dependence on mTOR suggests that PTEN and NF1 (neurofibromin) glial growth regulation requires TSC/Rheb (Ras homolog enriched in brain) control of mTOR function. In this report, we use a combination of genetic silencing in vitro and conditional mouse transgenesis approaches in vivo to demonstrate that neurofibromin regulates astrocyte cell growth and glioma formation in a TSC/Rheb-independent fashion. First, we show that Nf1 or Pten inactivation, but not Tsc1 loss or Rheb overexpression, increases astrocyte cell growth in vitro. Second, Nf1 -deficient increased mTOR signaling and astrocyte hyperproliferation is unaffected by Rheb shRNA silencing. Third, conditional Tsc1 inactivation or Rheb overexpression in glial progenitors of Nf1 +/− mice does not lead to glioma formation. Collectively, these findings establish TSC/Rheb-independent mechanisms for mTOR-dependent glial cell growth control and gliomagenesis relevant to the design of therapies for individuals with glioma.

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Mutant epidermal growth factor receptor displays increased signaling through the phosphatidylinositol-3 kinase/AKT pathway and promotes radioresistance in cells of astrocytic origin

Cited by 158 publications

References 26 publications

The ErbB signalling pathway: protein expression and prognostic value in epithelial ovarian cancer

The ErbB signalling pathway: protein expression and prognostic value in epithelial ovarian cancer

Akt1 Activation Can Augment Hypoxia-Inducible Factor-1α Expression by Increasing Protein Translation through a Mammalian Target of Rapamycin–Independent Pathway

Neurofibromatosis-1 regulates mTOR-mediated astrocyte growth and glioma formation in a TSC/Rheb-independent manner

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