Different Activation of Mitogen-Activated Protein Kinase and Akt Signaling Is Associated with Aggressive Phenotype of Human Meningiomas

Abstract

Purpose: Activation of intracellular signaling cascades has been implicated in the growth control of benign meningiomas, but their role for meningioma progression and outcome is unknown. Here we determined the expression and function of proteins involved in mitogenactivated protein kinase (MAPK) and phosphinositol-3 kinase (PI3K)/Akt signaling in benign, atypical, and malignant meningiomas and studied their association with clinicopathologic data including meningioma recurrence. Experimental Design: Expression of various MAPK and PI3K signaling proteins was determined in 70 primary meningiomas and, if present, in recurrent tumors by immunohistochemistry andWestern blotting.The expression patterns in primary and recurrent tumors were related to clinical data.The effect of MAPK and PI3K pathway inhibition on cell proliferation and apoptosis was determined using a primary malignant meningioma cell culture. Results: Atypical and malignant meningiomas showed higher levels of phospho-Akt compared with benign tumors, and their proliferation could be inhibited by PI3K blocking using wortmannin. PI3K inhibition did not induce apoptosis in malignant meningioma cells. In contrast, expression of phospho-Raf and phospho-MAPK was decreased in aggressive meningiomas compared with benign tumors, but MAPK inhibition by PD98059 resulted in tumor cell apoptosis and decreased proliferation. Reduced MAPK activation was associated with meningioma recurrence, and PI3K activation was associated with poor preclinical condition and brain invasion of malignant meningiomas. Conclusions: Both MAPK and PI3K/Akt pathways are activated at different levels in benign and malignant meningiomas. Activation of PI3K/Akt signaling contributes to the aggressive behavior of malignant meningiomas, whereas MAPK activation is involved in both proliferation and apoptosis of malignant meningiomas.

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

“…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.…”

Targeting homologous recombination using imatinib results in enhanced tumor cell chemosensitivity and radiosensitivity

“…Additionally, c-ABL has also been shown to be involved in the transcription and posttranslational modification of RAD51 (17). Because the platelet-derived growth factor-mitogenactivated protein kinase pathway is not always intact in malignant cell lines, our results suggest that our observed increases in cytotoxicity in vitro and in vivo following combined treatment with imatinib and DNA damaging agents may be due, in part, to inhibition of DNA repair (30,31). Indeed, initial Western blotting for phosphorylated platelet-derived growth factor receptor and mitogenactivated protein kinase among the tumor cell lines in this ) before irradiation and received daily PBS or imatinib i.p.…”

SPARC and Vav3 Expression in Meningioma: Factors Related to Prognosis

“…Higher p-Akt expression in grade II and III meningiomas indicate that the PI3K/Akt signaling pathway might be a potential target for meningioma therapy. The role of SPARC in some tumors might be associated with alterations in the methylation state of the SPARC promoter; thus, targeting SPARC may be an effective tumor therapy 14 . Vav3 is a guanine nucleotide exchange factor for Rho family GTPases.…”