title: The serine/threonine kinase Pim-2 is a novel anti-apoptotic mediator in myeloma cells.
abstract: Bone marrow stromal cells (BMSCs) and osteoclasts (OCs) confer multiple myeloma (MM) cell survival through elaborating factors. We demonstrate herein that IL-6 and TNF family cytokines, TNFα, BAFF and APRIL, but not IGF-1 cooperatively enhance the expression of the serine/threonine kinase Pim-2 in MM cells. BMSCs and OCs upregulate Pim-2 expression in MM cells largely via the IL-6/STAT3 and NF-κB pathway, respectively. Pim-2 short interfering RNA reduces MM cell viability in cocultures with BMSCs or OCs. Thus, upregulation of Pim-2 appears to be a novel anti-apoptotic mechanism for MM cell survival. Interestingly, the mammalian target of rapamycin inhibitor rapamycin further suppresses the MM cell viability in combination with the Pim-2 silencing. The Pim inhibitor (Z)-5-(4-propoxybenzylidene) thiazolidine-2, 4-dione and the PI3K inhibitor LY294002 cooperatively enhance MM cell death. The Pim inhibitor suppresses 4E-BP1 phosphorylation along with the reduction of Mcl-1 and c-Myc. Pim-2 may therefore become a new target for MM treatment.
authors.affiliation: Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, Tokushima, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Asano
authors.forename: A
authors.initials: A
authors.lastname: Nakano
authors.forename: A
authors.initials: A
authors.lastname: Oda
authors.forename: H
authors.initials: H
authors.lastname: Amou
authors.forename: M
authors.initials: M
authors.lastname: Hiasa
authors.forename: K
authors.initials: K
authors.lastname: Takeuchi
authors.forename: H
authors.initials: H
authors.lastname: Miki
authors.forename: S
authors.initials: S
authors.lastname: Nakamura
authors.forename: T
authors.initials: T
authors.lastname: Harada
authors.forename: S
authors.initials: S
authors.lastname: Fujii
authors.forename: K
authors.initials: K
authors.lastname: Kagawa
authors.forename: I
authors.initials: I
authors.lastname: Endo
authors.forename: K
authors.initials: K
authors.lastname: Yata
authors.forename: A
authors.initials: A
authors.lastname: Sakai
authors.forename: S
authors.initials: S
authors.lastname: Ozaki
authors.forename: T
authors.initials: T
authors.lastname: Matsumoto
authors.forename: M
authors.initials: M
authors.lastname: Abe
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009101:Multiple Myeloma / Q000201:enzymology* / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D017154:Stromal Cells / Q000187:drug effects / Q000201:enzymology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D002867:Chromones; C087000:EIF4EBP1 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; C489427:MYC protein, human; D009025:Morpholines; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D009363:Neoplasm Proteins; C490587:PIM2 protein, human; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D017346:Protein Serine-Threonine Kinases; D020123:Sirolimus