Pim Kinases Promote Migration and Metastatic Growth of Prostate Cancer Xenografts

Abstract

Background and methodsPim 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.ResultsWe 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.ConclusionsOur 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.

Phosphorylation of Notch1 by Pim kinases promotes oncogenic signaling in breast and prostate cancer cells

“…We have previously shown that Pim overexpression induces metastatic growth of PC-3-derived orthotopic xenografts in mice [25]. Immunostaining of the xenografted samples showed enhanced numbers of N1ICD-positive nuclei in tumors with stable Pim1 or Pim3 overexpression, while mock-transfected xenografts or Pim3-overexpressing xenografts from mice treated with the Pim inhibitor DHPCC-9 displayed fewer N1ICD-positive nuclei (Figure 9E-9F).…”

“…Shown are average tumor sizes from one representative experiment. E. N1ICD protein was stained from paraffin-embedded samples of orthotopic prostate xenografts that had been formed by mock-transfected PC-3 cells or cell stably overexpressing Pim1 or Pim3 [25]. Part of the mice with Pim-3-expressing xenografts had been daily treated with 50 mg/kg of DHPCC-9.…”

Bcl-2 and Bcl-xL mediate resistance to receptor tyrosine kinase-targeted therapy in lung and gastric cancer

“…4). We and others have shown that, in resistant cells, the PI3K/AKT and the MEK/ERK pathways are no longer regulated by RTK activity [15, 22, 27]. However, these pathways can still be blocked by their own inhibitors in resistant cells (Fig.…”

“…These cell lines include lung cancer cell lines HCC827 ( egfr deletion) [15], PC9 ( egfr deletion) [16], HCC4006 ( egfr mutation ) [17], EBC-1 ( met amplification) [18], H3122 ( eml4 - alk fusion) [19], and gastric cancer cell lines MKN45 ( met amplification) [7], NCI-N87 ( her2 amplification) [20], KATOIII ( fgfr2 amplification) [21]. We have previously shown that treatment of EBC-1 or MKN45 cells with the small-molecule MET TKIs induces the expression of Bcl-2 [22]. To determine whether this is a generalizable phenomenon, we treated HCC827, H3122, and NCI-N87 cells with the EGFR TKI gefitinib, the ALK TKI TAE684, and the dual HER2/EGFR TKI lapatinib, respectively.…”

Inhibition of autophagy enhances SMI-4a-induced growth inhibition and apoptosis of melanoma cells

“…Therefore, it is critical to identify the underlying molecular mechanisms in order to support the development of effective and novel treatments. PIM1 is overexpressed in several tumour types, including solid tumours and liquid malignancies, and contributes to tumour growth and metastasis [12]. Expression of PIM1 is associated with tumour aggressiveness, and it is a marker of poor prognosis in various tumours [13].…”