title: Pim Kinases Promote Migration and Metastatic Growth of Prostate Cancer Xenografts.
abstract: METHODS
  Pim family proteins are oncogenic kinases implicated in several types of cancer and involved in regulation of cell proliferation, survival as well as motility. Here we have investigated the ability of Pim kinases to promote metastatic growth of prostate cancer cells in two xenograft models for human prostate cancer. We have also evaluated the efficacy of Pim-selective inhibitors to antagonize these effects.
  
  
  RESULTS
  We show here that tumorigenic growth of both subcutaneously and orthotopically inoculated prostate cancer xenografts is enhanced by stable overexpression of either Pim-1 or Pim-3. Moreover, Pim-overexpressing orthotopic prostate tumors are highly invasive and able to migrate not only to the nearby prostate-draining lymph nodes, but also into the lungs to form metastases. When the xenografted mice are daily treated with the Pim-selective inhibitor DHPCC-9, both the volumes as well as the metastatic capacity of the tumors are drastically decreased. Interestingly, the Pim-promoted metastatic growth of the orthotopic xenografts is associated with enhanced angiogenesis and lymphangiogenesis. Furthermore, forced Pim expression also increases phosphorylation of the CXCR4 chemokine receptor, which may enable the tumor cells to migrate towards tissues such as the lungs that express the CXCL12 chemokine ligand.
  
  
  CONCLUSIONS
  Our results indicate that Pim overexpression enhances the invasive properties of prostate cancer cells in vivo. These effects can be reduced by the Pim-selective inhibitor DHPCC-9, which can reach tumor tissues without serious side effects. Thus, Pim-targeting therapies with DHPCC-9-like compounds may help to prevent progression of local prostate carcinomas to fatally metastatic malignancies.
authors.affiliation: Section of Genetics and Physiology, Department of Biology, University of Turku, 20500 Turku, Finland; Drug Research Doctoral Programme, University of Turku, 20520 Turku, Finland.
authors.forename: Niina M
authors.initials: NM
authors.lastname: Santio
authors.affiliation: Section of Genetics and Physiology, Department of Biology, University of Turku, 20500 Turku, Finland.
authors.forename: Sini K
authors.initials: SK
authors.lastname: Eerola
authors.affiliation: Institute of Biomedicine, Department of Medical Biochemistry and Genetics, University of Turku, 20520 Turku, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Paatero
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Jari
authors.initials: J
authors.lastname: Yli-Kauhaluoma
authors.affiliation: Institut de Chimie de Clermont-Ferrand, Université Clermont Auvergne, Université Blaise Pascal, 63000 Clermont-Ferrand, France; Centre National de la Recherche Scientifique, 63178 Aubiere, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Anizon
authors.affiliation: Institut de Chimie de Clermont-Ferrand, Université Clermont Auvergne, Université Blaise Pascal, 63000 Clermont-Ferrand, France; Centre National de la Recherche Scientifique, 63178 Aubiere, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Moreau
authors.affiliation: Institute of Biomedicine, Department of Cell Biology and Anatomy, University of Turku, 20520 Turku, Finland; Pharmatest Services Ltd, 20520 Turku, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Tuomela
authors.affiliation: Institute of Biomedicine, Department of Cell Biology and Anatomy, University of Turku, 20520 Turku, Finland.
authors.forename: Pirkko
authors.initials: P
authors.lastname: Härkönen
authors.affiliation: Section of Genetics and Physiology, Department of Biology, University of Turku, 20500 Turku, Finland.
authors.forename: Päivi J
authors.initials: PJ
authors.lastname: Koskinen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D042583:Lymphangiogenesis / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000473:pathology*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology; D011471:Prostatic Neoplasms / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism; D014183:Transplantation, Heterologous; D015027:Zebrafish
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D019718:Receptors, CXCR4; C496634:PIM1 protein, human; C499249:PIM3 protein, human; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim