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Carcinogenesis Advance Access originally published online on January 6, 2009
Carcinogenesis 2009 30(2):356-365; doi:10.1093/carcin/bgn287
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Overexpression of phospholipase D enhances matrix metalloproteinase-2 expression and glioma cell invasion via protein kinase C and protein kinase A/NF-{kappa}B/Sp1-mediated signaling pathways

Mi Hee Park, Bong-Hyun Ahn, Yong-Kil Hong1 and Do Sik Min*

Department of Molecular Biology, College of Natural Science, Pusan National University, 30 Jangjeon dong, Geumjeong gu, Busan 609-735, Korea
1 Department of Neurosurgery, Kangnam St Mary's Hospital, The Catholic University of Korea, Seoul 137-701, Korea

* To whom correspondence should be addressed. Tel: +82 51 510 3682; Fax: +82 51 513 9258; Email: minds{at}pusan.ac.kr

Glioblastoma is a severe type of primary brain tumor, and its highly invasive character is considered to be a major therapeutic obstacle. Phospholipase D (PLD) isozyme is overexpressed in various human tumor tissues and involved in tumorigenesis. However, the molecular mechanisms by which PLD enhances glioma invasion are unknown. In this study, we demonstrate that the increased expression of PLD and its enzymatic activity in the glioma stimulate the secretion and expression of matrix metalloproteinase (MMP)-2 and induce the invasiveness of glioma cells. The upregulation of MMP-2 induced by phosphatidic acid (PA), the product of PLD, was mediated by protein kinase C (PKC), protein kinase A (PKA), nuclear factor-{kappa}B (NF-{kappa}B) and Sp1 and it enhanced glioma cell invasion. PA activated PKC and PKA and induced the nuclear translocation and transactivation of NF-{kappa}B. PA also increased the binding of NF-{kappa}B and Sp1 to the MMP-2 promoter. Mutation of the NF-{kappa}B- or Sp1-binding sites significantly attenuated MMP-2 promoter activity. This is the first report to show that NF-{kappa}B and Sp1 are essential transcriptional factors linking PLD to MMP-2 upregulation, providing evidence that PLD contributes to glioma progression by enhancing MMP-2 expression and tumor cell invasion via PKC/PKA/NF-{kappa}B/Sp1-mediated signaling pathways.

Abbreviations: MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; mt, mutant; MT1, membrane type 1; NF-{kappa}B, nuclear factor-{kappa}B; PA, phosphatidic acid; PCR, polymerase chain reaction; PDTC, pyrrollidine dithiocarbamate; PKA, protein kinase A; PKC, protein kinase C; PLD, phospholipase D; siRNA, small-interfering RNA; wt, wild-type

Received June 11, 2008; revised November 19, 2008; accepted December 14, 2008.


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