title: Regulation of prostate stromal fibroblasts by the PIM1 protein kinase.
abstract: The PIM1 oncogene is over-expressed in human prostate cancer epithelial cells. Importantly, we observe that in human hyperplastic and cancerous prostate glands PIM1 is also markedly elevated in prostate fibroblasts, suggesting an important role for this kinase in epithelial/stromal crosstalk. The ability of PIM1 to regulate the biologic activity of stromal cells is demonstrated by the observation that expression of PIM1 kinase in human prostate fibroblasts increases the level and secretion of the extracellular matrix molecule, collagen 1A1 (COL1A1), the pro-inflammatory chemokine CCL5, and the platelet-derived growth factor receptors (PDGFR). PIM1 is found to regulate the transcription of CCL5. In co-cultivation assays where PIM1 over-expressing fibroblasts are grown with BPH1 prostate epithelial cells, PIM1 activity markedly enhances the ability of these fibroblasts to differentiate into myofibroblasts and express known markers of cancer-associated fibroblasts (CAFs). This differentiation can be reversed by the addition of small molecule PIM kinase inhibitors. Western blots demonstrate that PIM1 expression in prostate fibroblasts stimulates the phosphorylation of molecules that regulate 5'Cap driven protein translation, including 4EBP1 and eIF4B. Consistent with the hypothesis that the kinase controls translation of specific mRNAs in prostate fibroblasts, we demonstrate that PIM1 expression markedly increases the level of COL1A1 and PDGFRβ mRNA bound to polysomes. Together these results point on PIM1 as a novel factor in regulation of the phenotype and differentiation of fibroblasts in prostate cancer by controlling both the transcription and translation of specific mRNAs.
authors.affiliation: Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC 29425, United States; The Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, United States. Electronic address: zemskova@musc.edu.
authors.forename: Marina Y
authors.initials: MY
authors.lastname: Zemskova
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, United States; The Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, United States.
authors.forename: Jin H
authors.initials: JH
authors.lastname: Song
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, United States; The Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, United States.
authors.forename: Bo
authors.initials: B
authors.lastname: Cen
authors.affiliation: Department of Hematology-Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Javier
authors.initials: J
authors.lastname: Cerda-Infante
authors.affiliation: Department of Hematology-Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Viviana P
authors.initials: VP
authors.lastname: Montecinos
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, United States; The Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, United States. Electronic address: kraft@musc.edu.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Kraft
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D018920:Coculture Techniques; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000201:enzymology* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D010766:Phosphorylation; D011467:Prostate / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D017154:Stromal Cells / Q000473:pathology; D014158:Transcription, Genetic
chemical_list: C483024:CCL5 protein, human; D018946:Chemokine CCL5; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D018836:Inflammation Mediators; D012333:RNA, Messenger; D017479:Receptors, Platelet-Derived Growth Factor; D051573:Proto-Oncogene Proteins c-pim-1
keywords: CCL5; COL1A1; Myofibroblasts; PDGDRβ; PIM1 kinase; Prostate cancer