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Neoplasma Vol.54, p.517-526, 2007 |
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Title: Down-regulation of vinculin upon MK886-induced apoptosis in LN18 glioblastoma cells | ||
Author: A. M. MAGRO, A. D. MAGRO, C. CUNNINGHAM, M. R. MILLER | ||
Abstract: Glioblastomas are a type of malignant brain tumor and are among the most difficult cancers to treat. One strategy to treat
aggressive cancers is the use of drugs that target multiple signaling pathways. MK886 is a drug known to inhibit both 5-
lipoxygenase-activating-protein (FLAP) and peroxisome proliferator activated receptor-α (PPAR-α). The objectives of this
study were to investigate the ability of MK886 to induce apoptotic cell death in LN18 glioblastoma cells and to characterize
the cell death mechanisms. MK886 induced massive apoptotic LN18 cell death that was manifested by the release of
nucleosomes, annexinV binding to phosphatidylserine in the absence of nuclear staining, and changes in the fluorescent
intensity of Mito Tracker Deep Red 633 indicating changes in mitochondrial oxidative function and mass. The alteration of
the mitochondrial function implied that MK886 induced apoptosis in LN18 cells via a mitochondrial pathway. The broad
caspases inhibitor ZVAD-FMK inhibited MK886-induced nucleosome release, but not annexinV binding or MK886-altered
mitochondrial function. Real time RT-PCR demonstrated that LN18 cells expressed significant levels of FLAP and PPAR-
α mRNAs. A low level of arachidonate 5-lipoxygenase (ALOX-5) mRNA was detected, but little, if any, arachidonate 12-
lipoxygenase (ALOX-12) mRNA was present. In addition, MK886-induced apoptosis in LN18 cells was accompanied by
a decrease in the protein and mRNA levels of vinculin, but not other focal adhesion proteins. In summary, the data presented
here indicate that disruption of the actin-vinculin-cell-cytoskeleton matrix of the LN18 glioblastoma is a component of the
MK886 induced apoptosis. In addition, MK886 treated LN18 cells could provide one model in which to investigate drugs
that target lipoxygenase and PPAR-α pathways in the chemotherapeutic treatment of glioblastomas. |
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Keywords: Glioblastoma; Apoptosis; PPAR-α; FLAP; 5-Lipoxygenase; MK886 | ||
Year: 2007, Volume: 54, Issue: | Page From: 517, Page To: 526 | |
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