Abstract
Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple tumors in the central nervous system, most notably schwannomas and meningiomas. Mutational inactivation of NF2 is found in 40-60% of sporadic meningiomas, but the molecular mechanisms underlying malignant changes of meningioma cells remain unclear. Because group I p21-activated kinases (Paks) bind to and are inhibited by the NF2-encoded protein Merlin, we assessed the signaling and anti-tumor effects of three group-I specific Pak inhibitors - Frax597, 716 and 1036 - in NF2-/- meningiomas in vitro and in an orthotopic mouse model. We found that these Pak inhibitors suppressed the proliferation and motility of both benign (Ben-Men1) and malignant (KT21-MG1) meningiomas cells. In addition, we found a strong reduction in phosphorylation of Mek and S6, and decreased cyclin D1 expression in both cell lines after treatment with Pak inhibitors. Using intracranial xenografts of luciferase-expressing KT21-MG1 cells, we found that treated mice showed significant tumor suppression for all three Pak inhibitors. Similar effects were observed in Ben-Men1 cells. Tumors dissected from treated animals exhibited an increase in apoptosis without notable change in proliferation. Collectively, these results suggest that Pak inhibitors might be useful agents in treating NF2-deficient meningiomas.
Highlights
Meningiomas arise from arachnoid cap cells located in the arachnoid mater and represent the most common intracranial neoplasia, accounting for approximately 30% of central nervous system (CNS) tumors [1]
To understand the contribution by which p21-activated kinases (Paks) isoforms might be involved in the growth of meningioma cells, we examined a panel of 13 meningioma cells (11 primary and 2 immortalized) and 3 arachnoid cell lines
We found that Pak1 and Pak2 were much more abundant than Pak3 in both meningioma and arachnoidal cells, as determined by immunoblot (Fig. S1A)
Summary
Meningiomas arise from arachnoid cap cells located in the arachnoid mater and represent the most common intracranial neoplasia, accounting for approximately 30% of central nervous system (CNS) tumors [1]. Only 5% of meningiomas are categorized as anaplastic (grade III), some patients with grade I tumors progress to higher histological grade when they recur [2]. The oncogenic mechanisms involved in the transformation of meningioma cells remain to be elucidated, limiting the opportunity to develop targeted therapies. Meningiomas have been reported to occur in ~50% of neurofibromatosis type II (NF2) patients and are frequently multifocal, originating either in cranial or spinal locations [3]. Tumors associated with NF2 often display more aggressive histologic features than sporadic meningiomas [4, 5]. It has been inferred that other factors, such as additional genetic alterations may be responsible for progression within this population
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
