The serine/threonine kinase Pim-2 is a novel anti-apoptotic mediator in myeloma cells

Leukemia. 2011 Jul;25(7):1182-8. doi: 10.1038/leu.2011.60. Epub 2011 Apr 8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins / biosynthesis
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / physiology*
  • Cell Cycle Proteins
  • Cell Differentiation / drug effects
  • Cell Line
  • Chromones / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Interleukin-6 / metabolism
  • Morpholines / pharmacology
  • Multiple Myeloma / enzymology*
  • Multiple Myeloma / pathology
  • Myeloid Cell Leukemia Sequence 1 Protein
  • NF-kappa B / metabolism
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Osteoclasts / drug effects
  • Osteoclasts / enzymology
  • Phosphoproteins / metabolism
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Protein-Serine-Threonine Kinases / biosynthesis
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology*
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA Interference
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / pharmacology
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Sirolimus / pharmacology
  • Stromal Cells / drug effects
  • Stromal Cells / enzymology
  • Transfection
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • Cell Cycle Proteins
  • Chromones
  • EIF4EBP1 protein, human
  • IL6 protein, human
  • Interleukin-6
  • MYC protein, human
  • Morpholines
  • Myeloid Cell Leukemia Sequence 1 Protein
  • NF-kappa B
  • Neoplasm Proteins
  • PIM2 protein, human
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Protein-Serine-Threonine Kinases
  • Sirolimus