Overexpression of phospholipase D enhances matrix metalloproteinase-2 expression and glioma cell invasion via protein kinase C and protein kinase A/NF-kappaB/Sp1-mediated signaling pathways.
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-kappaB (NF-kappaB) and Sp1 and it enhanced glioma cell invasion. PA activated PKC and PKA and induced the nuclear translocation and transactivation of NF-kappaB. PA also increased the binding of NF-kappaB and Sp1 to the MMP-2 promoter. Mutation of the NF-kappaB- or Sp1-binding sites significantly attenuated MMP-2 promoter activity. This is the first report to show that NF-kappaB 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-kappaB/Sp1-mediated signaling pathways.
Park
Mi Hee
MH
Department of Molecular Biology, College of Natural Science, Pusan National University, Geumjeong gu, Busan, Korea.
Ahn
Bong-Hyun
BH
Hong
Yong-Kil
YK
Min
Do Sik
do S
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D005910:Glioma; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D016328:NF-kappa B / Q000502:physiology*; D009361:Neoplasm Invasiveness; D010739:Phospholipase D / Q000096:biosynthesis*; D011493:Protein Kinase C / Q000502:physiology*; D011494:Protein Kinases / Q000502:physiology*; D015398:Signal Transduction
D016328:NF-kappa B; D011494:Protein Kinases; C065999:Sp1 kinase; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D010739:Phospholipase D; D020778:Matrix Metalloproteinase 2