Prognostic relevance of MAPK expression in glioblastoma multiforme

Mawrin, Christian; Diete, Sabine; Treuheit, Tim; Kropf, Siegfried; Vorwerk, Christian K.; Boltze, Carsten; Kirches, Elmar; Firsching, Raimund; Dietzmann, Knut

doi:10.3892/ijo.23.3.641

Cited by 35 publications

(41 citation statements)

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“…Interestingly, patients with pancreatic tumors with high ERK levels had better survival and responded better to treatment (Chadha et al 2006), suggesting that some of the tumor suppressor functions of the ERK pathway could be reactivated in cancer patients. Likewise, in mammary carcinomas, phospho-ERK levels correlated with good prognosis and a less aggressive phenotype (Milde-Langosch et al 2005;Svensson et al 2005), and similar correlations were found in brain tumors as well (Mawrin et al 2003(Mawrin et al , 2005. We extend these observations here by showing that phospho-ERK levels were remarkably low in the most aggressive prostate tumors.…”

Section: Discussionsupporting

confidence: 74%

Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation

et al. 2013

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Constitutive activation of growth factor signaling pathways paradoxically triggers a cell cycle arrest known as cellular senescence. In primary cells expressing oncogenic ras, this mechanism effectively prevents cell transformation. Surprisingly, attenuation of ERK/MAP kinase signaling by genetic inactivation of Erk2, RNAimediated knockdown of ERK1 or ERK2, or MEK inhibitors prevented the activation of the senescence mechanism, allowing oncogenic ras to transform primary cells. Mechanistically, ERK-mediated senescence involved the proteasome-dependent degradation of proteins required for cell cycle progression, mitochondrial functions, cell migration, RNA metabolism, and cell signaling. This senescence-associated protein degradation (SAPD) was observed not only in cells expressing ectopic ras, but also in cells that senesced due to short telomeres. Individual RNAi-mediated inactivation of SAPD targets was sufficient to restore senescence in cells transformed by oncogenic ras or trigger senescence in normal cells. Conversely, the anti-senescence viral oncoproteins E1A, E6, and E7 prevented SAPD. In human prostate neoplasms, high levels of phosphorylated ERK were found in benign lesions, correlating with other senescence markers and low levels of STAT3, one of the SAPD targets. We thus identified a mechanism that links aberrant activation of growth signaling pathways and short telomeres to protein degradation and cellular senescence.

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Section: Discussionsupporting

confidence: 74%

Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation

et al. 2013

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“…However, the details of the mechanisms of action remain unclear, and this agent has not been studied fully in glioma cells. The Ras-Erk 1/2 signal transduction cascade is activated in nearly all cases of glioblastoma multiforme (10,11) and Akt is activated in f70% (12)(13)(14)(15). Moreover, evidence from our laboratory suggests that forced combined Ras and Akt activation in glial progenitors is sufficient to induce glioblastoma multiforme in mice (14).…”

Section: Introductionmentioning

confidence: 81%

Perifosine Inhibits Multiple Signaling Pathways in Glial Progenitors and Cooperates With Temozolomide to Arrest Cell Proliferation in Gliomas In vivo

Momota¹,

Nerio²,

2005

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Perifosine is an oral Akt inhibitor which exerts a marked cytotoxic effect on human tumor cell lines, and is currently being tested in several phase II trials for treatment of major human cancers. However, the efficacy of perifosine in human gliomas has not been established. As Akt is activated in f70% of human glioblastomas, we investigated the impact of perifosine on glia in culture and on a mouse glioma model in vivo. Here we show that perifosine strongly reduces phosphorylation levels of Akt and extracellular signal-regulated kinase (Erk) 1/2, induces cell cycle arrest in G 1 and G 2 , and causes dose-dependent growth inhibition of mouse glial progenitors in which Akt and/or Ras-Erk 1/2 pathways are activated. Furthermore, because temozolomide is a common oral alkylating agent used in the treatment of gliomas, we investigated the effect of perifosine in combination with temozolomide. We observed an enhanced effect when both were used in culture. With these results, we combined perifosine and temozolomide as treatment of platelet-derived growth factor B-driven gliomas in mice. Animal studies showed that perifosine and temozolomide combination therapy was more effective than temozolomide treatment alone (P < 0.01). These results indicate that perifosine is an effective drug in gliomas in which Akt and Ras-Erk 1/2 pathways are frequently activated, and may be a new candidate for glioma treatment in the clinic. (Cancer Res 2005; 65(16): 7429-35)

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“…RAS effector pathways also promote angiogenesis through transcriptional up-regulation of angiogenic factors and increased invasiveness through ERK-mediated regulation of matrix metalloproteinases and RAC-mediated effects on the cytoskeleton (32). High ERK expression correlates with poor prognosis in patients with glioblastoma multiforme (33). Indirect inhibition of RAF kinase by FTIs has shown benefit in glioma xenograft models (34).…”

Section: Discussionmentioning

confidence: 99%

AAL881, a Novel Small Molecule Inhibitor of RAF and Vascular Endothelial Growth Factor Receptor Activities, Blocks the Growth of Malignant Glioma

et al. 2006

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Malignant gliomas are highly proliferative and angiogenic cancers resistant to conventional therapies. Although RAS and RAF mutations are uncommon in gliomas, RAS activity is increased in gliomas. Additionally, vascular endothelial growth factor and its cognate receptors are highly expressed in gliomas. We now report that AAL881, a novel lowmolecular weight inhibitor of the kinase activities associated with B-RAF, C-RAF (RAF-1), and VEGF receptor-2 (VEGFR2), showed activity against glioma cell lines and xenografts. In culture, AAL881 inhibited the downstream effectors of RAF in a concentration-dependent manner, with inhibition of proliferation associated with a G 1 cell cycle arrest, induction of apoptosis, and decreased colony formation. AAL881 decreased the proliferation of bovine aortic endothelial cells as well as the tumor cell secretion of vascular endothelial growth factor and inhibited the invasion of glioma cells through an artificial extracellular matrix. Orally administered AAL881 was well tolerated with minimal weight loss in non-tumor-bearing mice. Established s.c. human malignant glioma xenografts grown in immunocompromised mice treated with a 10-day course of oral AAL881 exhibited growth delays relative to control tumors, frequently resulting in long-term complete regressions. AAL881 treatment extended the survival of immunocompromised mice bearing orthotopic glioma xenografts compared with placebo controls. The intraparenchymal portions of orthotopic AAL881-treated tumors underwent widespread necrosis consistent with vascular disruption compared with the subarachnoid elements. These effects are distinct from our prior experience with VEGFR2 inhibitors, suggesting that targeting RAF itself or in combination with VEGFR2 induces profound tumor responses in gliomas and may serve as a novel therapeutic approach in patients with malignant gliomas. (Cancer Res 2006; 66(17): 8722-30)

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Prognostic relevance of MAPK expression in glioblastoma multiforme

Cited by 35 publications

References 0 publications

Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation

Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation

Perifosine Inhibits Multiple Signaling Pathways in Glial Progenitors and Cooperates With Temozolomide to Arrest Cell Proliferation in Gliomas In vivo

AAL881, a Novel Small Molecule Inhibitor of RAF and Vascular Endothelial Growth Factor Receptor Activities, Blocks the Growth of Malignant Glioma

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