%0 Journal Article %1 Wille2014 %A Wille, Christoph %A Köhler, Conny %A Armacki, Milena %A Jamali, Arsia %A Gössele, Ulrike %A Pfizenmaier, Klaus %A Seufferlein, Thomas %A Eiseler, Tim %D 2014 %J Molecular biology of the cell %K 2014 izi pfizenmaier %N 3 %P 324--36 %R 10.1091/mbc.E13-06-0334 %T Protein kinase D2 induces invasion of pancreatic cancer cells by regulating matrix metalloproteinases. %U https://doi.org/10.1091/mbc.E13-06-0334 %V 25 %X 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. %@ 1939-4586 (Electronic)$\backslash$r1059-1524 (Linking)

@article{Wille2014, 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.}, added-at = {2023-06-29T13:07:55.000+0200}, author = {Wille, Christoph and K{\"{o}}hler, Conny and Armacki, Milena and Jamali, Arsia and G{\"{o}}ssele, Ulrike and Pfizenmaier, Klaus and Seufferlein, Thomas and Eiseler, Tim}, biburl = {https://puma.ub.uni-stuttgart.de/bibtex/2e74706df08a436595f18c353d4b95097/fabian}, doi = {10.1091/mbc.E13-06-0334}, interhash = {395b60c7150550000c385a8ac041ac5e}, intrahash = {e74706df08a436595f18c353d4b95097}, isbn = {1939-4586 (Electronic)$\backslash$r1059-1524 (Linking)}, issn = {1939-4586}, journal = {Molecular biology of the cell}, keywords = {2014 izi pfizenmaier}, month = feb, number = 3, pages = {324--36}, pmid = {24336522}, timestamp = {2023-06-29T13:07:55.000+0200}, title = {{Protein kinase D2 induces invasion of pancreatic cancer cells by regulating matrix metalloproteinases.}}, url = {https://doi.org/10.1091/mbc.E13-06-0334}, volume = 25, year = 2014 }