Date Published: June 15, 2015
Publisher: Public Library of Science
Author(s): Niina M. Santio, Sini K. Eerola, Ilkka Paatero, Jari Yli-Kauhaluoma, Fabrice Anizon, Pascale Moreau, Johanna Tuomela, Pirkko Härkönen, Päivi J. Koskinen, Jeffrey K. Harrison.
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.
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.
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.
The pim family genes were first identified as proviral integration sites for Moloney murine leukemia virus , but have later been shown to be involved in development of human lymphoid malignancies as well as solid tumors . The proteins encoded by the three pim family genes are serine/threonine-specific kinases that have been shown to promote tumorigenesis by increasing both proliferation and survival of cells [2,3]. More recently, we and others have also implicated them in the regulation of migration and invasion of adherent cancer cells [4–6], while results from clinical studies show association of abnormally high levels of Pim kinases with more malignant cancers of epithelial origin [7–9].
Here we show that PC-3 prostate cancer cells overexpressing either Pim-1 or Pim-3 kinases form larger xenograft tumors than the parental PC-3 cells. These results are well in line with previous observations on the ability of Pim-1 and Pim-2 to enhance growth of PC-3 cell-derived subcutaneous prostate cancer xenografts , while here we demonstrate that Pim-3 is also equally effective. More intriguingly, when orthotopically inoculated into mouse prostates, cells overexpressing Pim-1 or Pim-3 have an increased capacity to metastasize from the prostate-based tumors to other organs such as the lungs. In addition, one of the tested Pim-inhibitory compounds, DHPCC-9, is able to decrease Pim-dependent tumor growth as well as formation of metastases without severe side effects, suggesting that it is able to penetrate into tumor cells to inactivate Pim kinases there.
Taken together, we have shown that Pim kinases play an important role in cancer progression by increasing the potential of tumor cells to grow as well as to invade not only to the surrounding tissues but also much further into the body. In addition to enhancing angiogenesis and lymphangiogenesis, Pim kinases are likely to promote metastatic prostate cancer growth by employing the CXCL12/CXCR4 chemokine pathway. Furthermore, we have provided preliminary evidence for the safety and efficacy of the Pim-selective inhibitor DHPCC-9 as a promising compound to decrease Pim-induced cell proliferation and motility also in vivo. Such compounds are clearly needed to combat the fatal metastases associated with prostate cancer and other solid tumors.