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

¹ Department of Neurosurgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, 3-18-15, Kuramoto-cho, Tokushima, Japan 770-8503
² Department of Neurosurgery, Institute of Health Biosciences, the University of Tokushima Graduate School, Tokushima, Japan
³ Division of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan

^* To whom correspondence should be addressed. E-mail: kny1616{at}yahoo.co.jp.

	Abstract

Purpose: 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. Experimental Design: 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. Results: The protein expression of PML was significantly lower in GBM- than 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 NFB/p65 and c-FLIP gene expression was suppressed. Therefore, PML-induced apoptosis resulted from the suppression of the transcriptional activity of NFB/p65. PML overexpression decreased phosphorylated IB and nuclear NFB/p65 and increased the expression of the suppressor of cytokine signaling (SOCS)-1. A proteasome inhibitor blocked the reduction of activated p65 by PML. Conclusions: The reduction of PML is associated with the pathogenesis of GBM. PML induces caspase-8-dependent apoptosis via the repression of NFB activation by which PML facilitates the proteasomal degradation of activated p65 and the sequestration of p65 with IB in the cytoplasm. This novel mechanism of PML-regulated apoptosis may represent a therapeutic target for GBM.

Key Words: apoptosis, caspase, glioblastoma, NFB/p65, PML

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