Protein kinase D2 induces invasion of pancreatic cancer cells by regulating matrix metalloproteinases

Mol Biol Cell. 2014 Feb;25(3):324-36. doi: 10.1091/mbc.E13-06-0334. Epub 2013 Dec 11.

Abstract

Pancreatic cancer cell invasion, metastasis, and angiogenesis are major challenges for the development of novel therapeutic strategies. Protein kinase D (PKD) isoforms are involved in controlling tumor cell motility, angiogenesis, and metastasis. In particular PKD2 expression is up-regulated in pancreatic cancer, whereas PKD1 expression is lowered. We report that both kinases control pancreatic cancer cell invasive properties in an isoform-specific manner. PKD2 enhances invasion in three-dimensional extracellular matrix (3D-ECM) cultures by stimulating expression and secretion of matrix metalloproteinases 7 and 9 (MMP7/9), by which MMP7 is likely to act upstream of MMP9. Knockdown of MMP7/9 blocks PKD2-mediated invasion in 3D-ECM assays and in vivo using tumors growing on chorioallantois membranes. Furthermore, MMP9 enhances PKD2-mediated tumor angiogenesis by releasing extracellular matrix-bound vascular endothelial growth factor A, increasing its bioavailability and angiogenesis. Of interest, specific knockdown of PKD1 in PKD2-expressing pancreatic cancer cells further enhanced the invasive properties in 3D-ECM systems by generating a high-motility phenotype. Loss of PKD1 thus may be beneficial for tumor cells to enhance their matrix-invading abilities. In conclusion, we define for the first time PKD1 and 2 isoform-selective effects on pancreatic cancer cell invasion and angiogenesis, in vitro and in vivo, addressing PKD isoform specificity as a major factor for future therapeutic strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Proliferation
  • Chorioallantoic Membrane / cytology
  • Extracellular Matrix
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Matrix Metalloproteinase 7 / biosynthesis
  • Matrix Metalloproteinase 7 / genetics
  • Matrix Metalloproteinase 7 / metabolism
  • Matrix Metalloproteinase 9 / biosynthesis
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Neoplasm Invasiveness / genetics*
  • Neoplasm Metastasis / genetics
  • Neovascularization, Pathologic / genetics
  • Pancreatic Neoplasms / pathology*
  • Protein Kinase C / genetics*
  • Protein Kinase D2
  • Protein Kinases / genetics*
  • RNA Interference
  • RNA, Small Interfering
  • Vascular Endothelial Growth Factor A / biosynthesis
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Protein Kinase D2
  • RNA, Small Interfering
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Protein Kinases
  • protein kinase D
  • Protein Kinase C
  • MMP7 protein, human
  • Matrix Metalloproteinase 7
  • MMP9 protein, human
  • Matrix Metalloproteinase 9