Pim Kinases Promote Migration and Metastatic Growth of Prostate Cancer Xenografts

Niina M Santio; Sini K Eerola; Ilkka Paatero; Jari Yli-Kauhaluoma; Fabrice Anizon; Pascale Moreau; Johanna Tuomela; Pirkko Härkönen; Päivi J Koskinen

doi:10.1371/journal.pone.0130340

Pim Kinases Promote Migration and Metastatic Growth of Prostate Cancer Xenografts

PLoS One. 2015 Jun 15;10(6):e0130340. doi: 10.1371/journal.pone.0130340. eCollection 2015.

Authors

Niina M Santio¹, Sini K Eerola², Ilkka Paatero³, Jari Yli-Kauhaluoma⁴, Fabrice Anizon⁵, Pascale Moreau⁵, Johanna Tuomela⁶, Pirkko Härkönen⁷, Päivi J Koskinen²

Affiliations

¹ Section of Genetics and Physiology, Department of Biology, University of Turku, 20500 Turku, Finland; Drug Research Doctoral Programme, University of Turku, 20520 Turku, Finland.
² Section of Genetics and Physiology, Department of Biology, University of Turku, 20500 Turku, Finland.
³ Institute of Biomedicine, Department of Medical Biochemistry and Genetics, University of Turku, 20520 Turku, Finland.
⁴ Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland.
⁵ 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.
⁶ Institute of Biomedicine, Department of Cell Biology and Anatomy, University of Turku, 20520 Turku, Finland; Pharmatest Services Ltd, 20520 Turku, Finland.
⁷ Institute of Biomedicine, Department of Cell Biology and Anatomy, University of Turku, 20520 Turku, Finland.

Abstract

Background and 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Cell Movement
Cell Proliferation
Chemokine CXCL12 / metabolism
Heterografts
Humans
Lymphangiogenesis / physiology
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Metastasis / pathology*
Neoplasm Transplantation
Neovascularization, Pathologic / pathology
Prostatic Neoplasms / pathology*
Protein Kinase Inhibitors / pharmacology
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / biosynthesis
Protein Serine-Threonine Kinases / metabolism*
Proto-Oncogene Proteins / antagonists & inhibitors
Proto-Oncogene Proteins / biosynthesis
Proto-Oncogene Proteins / metabolism*
Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
Proto-Oncogene Proteins c-pim-1 / biosynthesis
Proto-Oncogene Proteins c-pim-1 / metabolism*
Receptors, CXCR4 / metabolism
Transplantation, Heterologous
Zebrafish

Substances

CXCL12 protein, human
CXCR4 protein, human
Chemokine CXCL12
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Receptors, CXCR4
PIM1 protein, human
PIM3 protein, human
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-pim-1
proto-oncogene proteins pim

Grants and funding

This work was supported by the Academy of Finland (grant 121533 to PJK, grant 269541 to PH), TULI Program of the University of Turku (PJK), Sigrid Jusélius Foundation (PH), FinPharma Doctoral Program (NMS), Emil Aaltonen Foundation (NMS), Cancer Organizations for the Western Finland (NMS), Orion-Farmos Research Foundation (NMS), Finnish Cultural Foundation (NMS), Turku University Foundation (SKE), and Walter och Lisi Wahls Stiftelse för Naturvetenskaplig Forskning (JYK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Johanna Tuomela was employed by Pharmatest Services Ltd for a period during the study. Pharmatest did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of JT is articulated in the ‘author contributions’ section.