title: The essential role of PIM kinases in sarcoma growth and bone invasion.
abstract: PIM kinases are a family of serine/threonine kinases composed of three different isoforms (PIM1, PIM 2 and PIM 3) that are highly homologous. Their expression is mediated by the JAK/STAT signalling pathway, providing survival and cell cycle transition signals. PIM kinases are heavily targeted for anticancer drug discovery. However, very little is known about the relative contribution of the different isoforms to the tumourigenesis process in vivo, and how their individual inhibition might affect tumour growth. Taking advantage of genetically modified mice, we explored whether the inhibition of specific isoforms is required to prevent sarcomas induced by 3-methylcholanthrene carcinogenic treatment. We found that absence of Pim2 and Pim3 greatly reduced sarcoma growth to a similar extent to the absence of all three isoforms. This model of sarcoma generally produces bone invasion by the tumour cells. Lack of Pim2 and Pim3 reduced tumour-induced bone invasion by 70%, which is comparable with the reduction of tumour-induced bone invasion in the absence of all three isoforms. Similar results were obtained in mouse embryonic fibroblasts (MEFs) derived from these knockout (KO) mice, where double Pim2/3 KO MEFs already showed reduced proliferation and were resistant to oncogenic transformation by the RAS oncogene. Our data also suggest an important role of Gsk3β phosphorylation in the process of tumourigenesis.
authors.affiliation: Experimental Therapeutics Programme, Spanish National Cancer Research Centre Madrid, Spain.
authors.forename: Maja
authors.initials: M
authors.lastname: Narlik-Grassow
authors.forename: Carmen
authors.initials: C
authors.lastname: Blanco-Aparicio
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Cecilia
authors.forename: Sandra
authors.initials: S
authors.lastname: Peregrina
authors.forename: Beatriz
authors.initials: B
authors.lastname: Garcia-Serelde
authors.forename: Sandra
authors.initials: S
authors.lastname: Muñoz-Galvan
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.forename: Amancio
authors.initials: A
authors.lastname: Carnero
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000473:pathology*; D002273:Carcinogens / Q000633:toxicity; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D008748:Methylcholanthrene / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism*; D012513:Sarcoma, Experimental / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*
chemical_list: D002273:Carcinogens; D008748:Methylcholanthrene; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim