title: The PIM1 kinase promotes prostate cancer cell migration and adhesion via multiple signalling pathways.
abstract: The ability of cells to migrate and form metastases is one of the fatal hallmarks of cancer that can be conquered only with better understanding of the molecules and regulatory mechanisms involved. The oncogenic PIM kinases have been shown to support cancer cell survival and motility, but the PIM-regulated pathways stimulating cell migration and invasion are less well characterized than those affecting cell survival. Here we have identified the glycogen synthase kinase 3β (GSK3B) and the forkhead box P3 (FOXP3) transcription factor as direct PIM targets, whose tumour-suppressive effects in prostate cancer cells are inhibited by PIM-induced phosphorylation, resulting in increased cell migration. Targeting GSK3B is also essential for the observed PIM-enhanced expression of the prostaglandin-endoperoxide synthase 2 (PTGS2), which is an important regulator of both cell migration and adhesion. Accordingly, selective inhibition of PIM activity not only reduces cell migration, but also affects integrin-mediated cell adhesion. Taken together, these data provide novel mechanistic insights on how and why patients with metastatic prostate cancer may benefit from therapies targeting PIM kinases, and how such approaches may also be applicable to inflammatory conditions.
authors.affiliation: Section of Genetics and Physiology, Department of Biology, University of Turku, 20500 Turku, Finland; Drug Research Doctoral Programme, University of Turku, 20520 Turku, Finland.
authors.forename: Niina M
authors.initials: NM
authors.lastname: Santio
authors.affiliation: Department of Biochemistry, University of Turku, 20500 Turku, Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Salmela
authors.affiliation: Section of Genetics and Physiology, Department of Biology, University of Turku, 20500 Turku, Finland.
authors.forename: Heidi
authors.initials: H
authors.lastname: Arola
authors.affiliation: Section of Genetics and Physiology, Department of Biology, University of Turku, 20500 Turku, Finland.
authors.forename: Sini K
authors.initials: SK
authors.lastname: Eerola
authors.affiliation: Department of Biochemistry, University of Turku, 20500 Turku, Finland.
authors.forename: Jyrki
authors.initials: J
authors.lastname: Heino
authors.affiliation: Section of Genetics and Physiology, Department of Biology, University of Turku, 20500 Turku, Finland.
authors.forename: Eeva-Marja
authors.initials: EM
authors.lastname: Rainio
authors.affiliation: Section of Genetics and Physiology, Department of Biology, University of Turku, 20500 Turku, Finland. Electronic address: paivi.koskinen@utu.fi.
authors.forename: Päivi J
authors.initials: PJ
authors.lastname: Koskinen
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D002465:Cell Movement; D051858:Forkhead Transcription Factors / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051573:Proto-Oncogene Proteins c-pim-1 / Q000502:physiology*; D015398:Signal Transduction
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1; D038362:Glycogen Synthase Kinase 3
keywords: FoxP3; GSK3B; Integrins; PIM1; PTGS2; Prostate cancer