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

Pim Kinases Promote Migration and Metastatic Growth of Prostate Cancer Xenografts.

Author information

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.

PMID:
26075720
PMCID:
PMC4467846
DOI:
10.1371/journal.pone.0130340
[Indexed for MEDLINE]
Free PMC Article

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