Abstract
Mantle cell lymphoma (MCL) is characterized by the uncontrolled overexpression of cyclin D1. Styryl sulfonyl compounds have shown potent antitumor activity against MCL by inducing cell-cycle arrest and apoptosis. However, the exact molecular mechanism by which these compounds function is yet to be elucidated. Here, we show that the prototypical styryl sulfonyl compound ON 01910.Na decreased cyclin D1 and c-Myc protein levels in MCL cells, whereas mRNA levels of cyclin D1 were minimally affected. Notably, ON 01910.Na suppressed eukaryotic translation initiation factor 4E (eIF4E)-mediated cyclin D1 mRNA translation, decreased levels of phosphorylated Akt, mammalian target of Rapamycin (mTOR) and eIF4E-binding protein (eIF4E-BP), lowered the cap site binding activity of eIF4E and directly inhibited activity of phosphatidylinositol-3 kinase (PI-3K). Analysis of apoptotic signaling pathways revealed that ON 01910.Na induced the release of cytochrome c from mitochondria, altered expression of Bcl-2 family of proteins and stimulated activation of caspases. Taken together, styryl sulfonyls can cause a rapid decrease of cyclin D1 by blocking cyclin D1 mRNA translation through inhibition of the PI-3K/Akt/mTOR/eIF4E-BP signaling pathway and triggering a cytochrome c-dependent apoptotic pathway in MCL cells.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Cell Line, Tumor
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Cyclin D1 / genetics*
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Eukaryotic Initiation Factor-4E / physiology
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Extracellular Signal-Regulated MAP Kinases / physiology
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Forkhead Box Protein O1
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Forkhead Transcription Factors / metabolism
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Glycine / analogs & derivatives*
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Glycine / pharmacology
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Humans
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Lymphoma, Mantle-Cell / drug therapy*
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Lymphoma, Mantle-Cell / genetics
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Lymphoma, Mantle-Cell / pathology
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Mitogen-Activated Protein Kinase Kinases / physiology
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation
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Protein Biosynthesis / drug effects*
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Protein Kinases / physiology
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Proto-Oncogene Proteins c-akt / physiology
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Proto-Oncogene Proteins c-myc / antagonists & inhibitors
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Signal Transduction / drug effects
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Sulfones / pharmacology*
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TOR Serine-Threonine Kinases
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p38 Mitogen-Activated Protein Kinases / physiology
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raf Kinases / physiology
Substances
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Antineoplastic Agents
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CCND1 protein, human
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Eukaryotic Initiation Factor-4E
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FOXO1 protein, human
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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MYC protein, human
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins c-myc
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Sulfones
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Cyclin D1
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ON 01910
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Protein Kinases
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MTOR protein, human
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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raf Kinases
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Extracellular Signal-Regulated MAP Kinases
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p38 Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase Kinases
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Glycine