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.

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

Grant support

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.