Abstract
Proviral integration site for Moloney murine leukemia virus (Pim) kinases are serine/threonine/tyrosine kinases and oncoproteins that promote tumor progression. Three isoforms of Pim kinases have been identified and are known to phosphorylate numerous substrates, with regulatory functions in transcription, translation, cell cycle, and survival pathways. These kinases are involved in production, proliferation, and survival of normal B cells and are overexpressed in B-cell malignancies such as mantle cell lymphoma (MCL). SGI-1776 is a small molecule and Pim kinase inhibitor with selectivity for Pim-1. We hypothesize that Pim kinase function can be inhibited by SGI-1776 in MCL and that inhibition of phosphorylation of downstream substrates will disrupt transcriptional, translational, and cell cycle processes and promote cell death. SGI-1776 treatment in 4 MCL cell lines resulted in apoptosis induction. Phosphorylation of transcription (c-Myc) and translation targets (4E-BP1), tested in Jeko-1 and Mino, was declined. Consistent with these data, Mcl-1 and cyclin D1 protein levels were decreased. Importantly, similar to cell line data, MCL primary cells but not normal cells showed similar inhibition of substrate phosphorylation and cytotoxicity from SGI-1776 treatment. Genetic knockdown of Pim-1/Pim-2 affected similar proteins in MCL cell lines. Collectively these data demonstrate Pim kinases as therapeutic targets in MCL.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Apoptosis / genetics
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Cell Cycle / drug effects
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Cell Cycle / genetics
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Cell Cycle Proteins
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Cell Line, Tumor
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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Gene Expression Regulation, Neoplastic
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Humans
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Imidazoles / pharmacology*
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Lymphoma, Mantle-Cell / drug therapy*
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Lymphoma, Mantle-Cell / genetics
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Lymphoma, Mantle-Cell / metabolism
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Mice
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Myeloid Cell Leukemia Sequence 1 Protein
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Phosphorylation
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Protein Biosynthesis / drug effects
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Protein Kinase Inhibitors / pharmacology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism
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Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-pim-1 / genetics
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Proto-Oncogene Proteins c-pim-1 / metabolism
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Pyridazines / pharmacology*
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RNA, Small Interfering / genetics
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Signal Transduction
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Transcription, Genetic / drug effects
Substances
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents
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CCND1 protein, human
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Cell Cycle Proteins
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EIF4EBP1 protein, human
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Imidazoles
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MYC protein, human
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Mcl1 protein, mouse
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Myeloid Cell Leukemia Sequence 1 Protein
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PIM2 protein, human
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Phosphoproteins
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Proto-Oncogene Proteins c-myc
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Pyridazines
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RNA, Small Interfering
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SGI 1776
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Cyclin D1
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PIM1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-pim-1