Promyelocytic leukemia protein induces apoptosis due to caspase-8 activation via the repression of NF B activation in glioblastoma

Department of Neurosurgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Tokushima, Japan.
Neuro-Oncology (Impact Factor: 5.56). 10/2008; 11(2):132-41. DOI: 10.1215/15228517-2008-083
Source: PubMed Central


Promyelocytic leukemia (PML) protein plays an essential role in the induction of apoptosis; its expression is reduced in various
cancers. As the functional roles of PML in glioblastoma multiforme (GBM) have not been clarified, we assessed the expression
of PML protein in GBM tissues and explored the mechanisms of PML-regulated cell death in GBM cells. We examined the PML mRNA level and the expression of PML protein in surgical GBM specimens. PML-regulated apoptotic mechanisms in GBM cells transfected
with plasmids expressing the PML gene were examined. The protein expression of PML was significantly lower in GBM than in non-neoplastic tissues; approximately
10% of GBM tissues were PML-null. The PML mRNA levels were similar in both tissue types. The overexpression of PML activated caspase-8 and induced apoptosis in GBM
cells. In these cells, PML decreased the expression of transactivated forms of NFκB/p65, and c-FLIP gene expression was suppressed. Therefore, PML-induced apoptosis resulted from the suppression of the transcriptional activity
of NFκB/p65. PML overexpression decreased phosphorylated IκBα and nuclear NFκB/p65 and increased the expression of the suppressor
of cytokine signaling (SOCS-1). A proteasome inhibitor blocked the reduction of activated p65 by PML. The reduction of PML
is associated with the pathogenesis of GBM. PML induces caspase-8–dependent apoptosis via the repression of NFκB activation
by which PML facilitates the proteasomal degradation of activated p65 and the sequestration of p65 with IκBα in the cytoplasm.
This novel mechanism of PML-regulated apoptosis may represent a therapeutic target for GBM.

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Available from: Kazuhito Matsuzaki, Aug 07, 2014
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