Fatty acid synthase as a novel target for meningioma therapy.
High levels of fatty acid synthase (FAS) expression have been reported in hormone receptor-positive tumors, including prostate, breast, and ovarian cancers, and its inhibition reduces tumor growth in vitro and in vivo. Similar to other hormone receptor-positive tumor types, meningiomas are progesterone receptor- and estrogen receptor-immunoreactive brain tumors. To define the role of FAS in human meningioma growth control, we first analyzed the FAS expression using a tissue microarray containing 38 meningiomas and showed increased FAS expression in 70% of atypical WHO grade II and anaplastic WHO grade III meningiomas compared with 10% of benign WHO grade I tumors. We next confirmed this finding by real-time PCR and Western blotting. Second, we demonstrated that treatment with the FAS inhibitor, cerulenin (Cer), significantly decreased meningioma cell survival in vitro. Third, we showed that Cer treatment reduced FAS expression by modulating Akt phosphorylation (activation). Fourth, we demonstrated that Cer treatment of mice bearing meningioma xenografts resulted in significantly reduced tumor volumes associated with increased meningioma cell death. Collectively, our data suggest that the increased FAS expression in human meningiomas represents a novel therapeutic target for the treatment of unresectable or malignant meningioma.
Department of Neuropathology, Otto-von-Guericke-University Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany.
Daniela
D
Haase
Stefan
S
Schmidl
Christian
C
Ewald
Rolf
R
Kalff
Christian
C
Huebner
Raimund
R
Firsching
Gerburg
G
Keilhoff
Matthias
M
Evert
Werner
W
Paulus
David H
DH
Gutmann
Anita
A
Lal
Christian
C
Mawrin
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002569:Cerulenin / Q000494:pharmacology*; D053938:DNA Fragmentation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D064429:Fatty Acid Synthases / Q000378:metabolism*; D054872:Fatty Acid Synthesis Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008577:Meningeal Neoplasms / Q000201:enzymology* / Q000473:pathology; D008579:Meningioma / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D023041:Xenograft Model Antitumor Assays
D054872:Fatty Acid Synthesis Inhibitors; D012333:RNA, Messenger; D002569:Cerulenin; D064429:Fatty Acid Synthases