title: The phosphatase of regenerating liver-3 (PRL-3) is important for IL-6-mediated survival of myeloma cells.
abstract: Multiple myeloma (MM) is a neoplastic proliferation of bone marrow plasma cells. PRL-3 is a phosphatase induced by interleukin (IL)-6 and other growth factors in MM cells and promotes MM-cell migration. PRL-3 has also been identified as a marker gene for a subgroup of patients with MM. In this study we found that forced expression of PRL-3 in the MM cell line INA-6 led to increased survival of cells that were depleted of IL-6. It also caused redistribution of cells in cell cycle, with an increased number of cells in G2M-phase. Furthermore, forced PRL-3 expression significantly increased phosphorylation of Signal transducer and activator of transcription (STAT) 3 both in the presence and the absence of IL-6. Knockdown of PRL-3 with shRNA reduced survival in MM cell line INA-6. A pharmacological inhibitor of PRL-3 reduced survival in the MM cell lines INA-6, ANBL-6, IH-1, OH-2 and RPMI8226. The inhibitor also reduced survival in 9 of 9 consecutive samples of purified primary myeloma cells. Treatment with the inhibitor down-regulated the anti-apoptotic protein Mcl-1 and led to activation of the intrinsic apoptotic pathway. Inhibition of PRL-3 also reduced IL-6-induced phosphorylation of STAT3. In conclusion, our study shows that PRL-3 is an important mediator of growth factor signaling in MM cells and hence possibly a good target for treatment of MM.
authors.affiliation: K. G. Jebsen Center for Myeloma Research, Trondheim, Norway.|Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.|Clinic of Medicine, St Olavs University Hospital, Trondheim, Norway.
authors.forename: Tobias S
authors.initials: TS
authors.lastname: Slørdahl
authors.affiliation: K. G. Jebsen Center for Myeloma Research, Trondheim, Norway.|Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Pegah
authors.initials: P
authors.lastname: Abdollahi
authors.affiliation: K. G. Jebsen Center for Myeloma Research, Trondheim, Norway.|Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Esten N
authors.initials: EN
authors.lastname: Vandsemb
authors.affiliation: K. G. Jebsen Center for Myeloma Research, Trondheim, Norway.|Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Christoph
authors.initials: C
authors.lastname: Rampa
authors.affiliation: K. G. Jebsen Center for Myeloma Research, Trondheim, Norway.|Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Kristine
authors.initials: K
authors.lastname: Misund
authors.affiliation: K. G. Jebsen Center for Myeloma Research, Trondheim, Norway.|Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.|Department of Hematology, St Olavs University Hospital, Trondheim, Norway.
authors.forename: Katarzyna A
authors.initials: KA
authors.lastname: Baranowska
authors.affiliation: K. G. Jebsen Center for Myeloma Research, Trondheim, Norway.|Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Marita
authors.initials: M
authors.lastname: Westhrin
authors.affiliation: K. G. Jebsen Center for Myeloma Research, Trondheim, Norway.|Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.|Department of Hematology, St Olavs University Hospital, Trondheim, Norway.
authors.forename: Anders
authors.initials: A
authors.lastname: Waage
authors.affiliation: K. G. Jebsen Center for Myeloma Research, Trondheim, Norway.|Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.|Department of Pediatrics, St Olavs University Hospital, Trondheim, Norway.
authors.forename: Torstein B
authors.initials: TB
authors.lastname: Rø
authors.affiliation: K. G. Jebsen Center for Myeloma Research, Trondheim, Norway.|Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.|Department of Immunology and Transfusion Medicine, St Olavs University Hospital, Trondheim, Norway.
authors.forename: Magne
authors.initials: M
authors.lastname: Børset
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D018920:Coculture Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D015850:Interleukin-6 / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000494:pharmacology; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D015850:Interleukin-6; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D011506:Proteins; D050796:STAT3 Transcription Factor; C073882:phosphoprotein phosphatase inhibitor 1; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases
keywords: IL-6; PRL-3; PTP4A3; STAT-3; multiple myeloma