The activation of ERK1/2 MAP kinases in glioblastoma pathobiology and its relationship with EGFRamplification

Abstract

The ERK1/2 activated protein kinase (MAPK) pathway is a critical signaling system that mediates ligand-stimulated signals for the induction of cell proliferation, differentiation and survival, involved in malignant transformation. The purpose of this study was to determine the activation of ERK1/2 in this tumor, and to determine the relationship of ERK1/2 activation with the amplification/overexpression of EGFR as well as with 9p21 locus gene alterations, both of which are genetic factors frequently associated with glioblastoma. We used immunohistochemistry and Western blot analysis to analyze the activation of ERK1/2 in 22 patients with glioblastoma, and we studied the amplification/overexpression of EGFR; as well as the molecular alterations in 9p21 locus genes. Positive immunostaining ERK1/2 was observed in 86.4% of the tumors, displaying mainly nuclear immunolocalization; and by immunoblotting, ERK1/2 was activated in 68% of the cases. The 70% of cases with EGFR amplification presented activated ERK1/2. The joint presence of amplified EGFR and alterations in the 9p21 genes was observed in 50% of the cases, whereas the simultaneous occurrence of these two phenomena with the activation of ERK1/2 was observed in 40% of the cases. Our results suggest that the activation of ERK1/2 is implicated in the pathobiology of glioblastoma. This activation of ERK1/2 is probably related in part to the amplification of EGFR as well as to alterations in 9p21 locus genes (homozygous deletion and promoter methylation). However, the activation of ERK1/2 also involves pathways that are independent of the EGFR.

Caveolin-1 is a negative regulator of tumor growth in glioblastoma and modulates chemosensitivity to temozolomide

“…Although it has long been known that Cav-1 serves to negatively regulate the activity of p42/p44 (ERK1/2) signaling proteins of the MAPK pathway, our evidence also suggests it has the capability to sequester PI3K and mTOR activity 20 - 26 . This is notable due to the fact that ERK, PI3K and mTOR signaling axes are frequently upregulated in GBM, suggesting that loss of Cav-1 could lead to unchecked activation of these pathways 27 - 31 . Two of the most commonly silenced genes in GBM are the tumor suppressor proteins PTEN and TP53, which serve to antagonize the PI3K/AKT/mTOR pathway and regulate cell cycle response to DNA damage and cell death, respectively 32 .…”

Expressions of matrix metalloproteinase-7 and matrix metalloproteinase-14 associated with the activation of extracellular signal-regulated kinase1/2 in human brain gliomas of different pathological grades

“…Moreover, blocking ERK1/2 proteins activation using specific MEK inhibitor PD098059 can lead to the reduction in the transcription and secretion activity of MMPs in tumor cells [18,27]. Recently, several studies have confirmed that ERK1/2 is activated in human brain gliomas [28,29], but the activation status of ERK1/2 in human brain gliomas of different pathological grades is still unknown.…”

Glioma-specific Cation Conductance Regulates Migration and Cell Cycle Progression

“…Activation of ERK1/2 is classically downstream of the EGFR, which is overexpressed in most GBM tumors (45), and ERK1/2 phosphorylation is a key signaling event controlling migration and proliferation of multiple cancer cells, including gliomas (10,23,46). However, activation of ERK1/2 in the absence of EGFR amplification has been reported, suggesting that nonclassical pathways are also involved in the regulation of this important transcriptional regulator (45). Down-regulation of ERK1/2 is intimately associated with cell cycle inhibition and accumulation of p27…”