title: Protein kinase D2 induces invasion of pancreatic cancer cells by regulating matrix metalloproteinases.
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.
authors: Department of Internal Medicine I, Ulm University, D-89081 Ulm, Germany Department of Internal Medicine I, Martin-Luther University Halle-Wittenberg, D-06120 Halle (Saale), Germany Institute for Cell Biology and Immunology, University of Stuttgart, D-70569 Stuttgart, Germany.
authors: Christoph
authors: C
authors: Wille
authors: Conny
authors: C
authors: Köhler
authors: Milena
authors: M
authors: Armacki
authors: Arsia
authors: A
authors: Jamali
authors: Ulrike
authors: U
authors: Gössele
authors: Klaus
authors: K
authors: Pfizenmaier
authors: Thomas
authors: T
authors: Seufferlein
authors: Tim
authors: T
authors: Eiseler
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D049033:Chorioallantoic Membrane / Q000166:cytology; D005109:Extracellular Matrix; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D020783:Matrix Metalloproteinase 7 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009362:Neoplasm Metastasis / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011493:Protein Kinase C / Q000235:genetics*; D000091283:Protein Kinase D2; D011494:Protein Kinases / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D000091283:Protein Kinase D2; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D011494:Protein Kinases; C089212:protein kinase D; D011493:Protein Kinase C; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9