Toll-like receptor-4 is expressed in meningiomas and mediates the antiproliferative action of paclitaxel.
Meningiomas are the second most common type of brain and CNS tumors by histology. Surgery and radiotherapy are main treatment options, but meningiomas may be impossible to adequately resect or may regrow after surgery. In spite of many experimental attempts, there is no generally accepted chemotherapeutic approach. We have studied in a series of meningiomas the expression of the Toll-like receptor 4 (TLR4), which apart from its major role as a key factor of the innate immune system, is believed to play a role in tumorigenesis. All meningiomas studied expressed TLR4 mRNA and protein at variable degree. Paclitaxel, a ligand of TLR4, exhibited a dose- and time-dependent growth suppression in both monolayer and spheroid meningioma cell cultures. The knockdown of TLR4 with siRNA in meningioma cell cultures abrogated the inhibitory effect of paclitaxel. The suppressive action of paclitaxel on meningioma cell growth was enhanced in the presence of fluvastatin or the mitogen-actvated protein kinase (ERK1/2) inhibitor PD98059. At least part of the growth suppressive effect was mediated by the induction of apoptosis in meningioma cells by paclitaxel alone or in combination with fluvastatin. In conclusion, our in vitro results suggest that paclitaxel alone or in combination with other inhibitors of cell growth (statins, MAPK inhibitors) could provide a potential tool for the treatment of TLR4 expressing meningiomas.
Tichomirowa
Maria A
MA
Department of Endocrinology, Max-Planck-Institute of Psychiatry, Munich, Germany. renner@mpipsykl.mpg.de
Theodoropoulou
Marily
M
Daly
Adrian F
AF
Yassouridis
Alexander
A
Hansen
Sabine
S
Lu
Jie
J
Lange
Manfred
M
Goldbrunner
Roland H
RH
Stalla
Günter K
GK
Renner
Ulrich
U
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage; D007150:Immunohistochemistry; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D008577:Meningeal Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008579:Meningioma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D018874:Spheroids, Cellular; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis* / Q000235:genetics; D014407:Tumor Cells, Cultured
D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D034741:RNA, Small Interfering; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D000077340:Fluvastatin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D017239:Paclitaxel