Styryl sulfonyl compounds inhibit translation of cyclin D1 in mantle cell lymphoma cells

• Published in: Oncogene Vol. 28; no. 12; pp. 1518 - 1528
• Main Authors: Prasad, A, Park, I-W, Allen, H, Zhang, X, Reddy, M V R, Boominathan, R, Reddy, E P, Groopman, J E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26-03-2009; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Antineoplastic Agents - pharmacology; Antitumor activity; Antitumor agents; Apoptosis; Apoptosis - drug effects; Bcl-2 protein; c-Myc protein; Cell Biology; Cell cycle; Cell Line, Tumor; Chemotherapy; Cyclin D1; Cyclin D1 - genetics; Cytochrome; Cytochrome c; Drug therapy; Eukaryotic Initiation Factor-4E - physiology; Extracellular Signal-Regulated MAP Kinases - physiology; Forkhead Box Protein O1; Forkhead Transcription Factors - metabolism; Gene expression; Glycine - analogs & derivatives; Glycine - pharmacology; Health aspects; Human Genetics; Humans; Hypoglycemic sulfonylureas; Initiation factor eIF-4E; Internal Medicine; Kinases; Lymphoma; Lymphoma, Mantle-Cell - drug therapy; Lymphoma, Mantle-Cell - genetics; Lymphoma, Mantle-Cell - pathology; Mantle cell lymphoma; Medicine; Medicine & Public Health; Mitochondria; Mitogen-Activated Protein Kinase Kinases - physiology; mRNA; Myc protein; Non-Hodgkin's lymphomas; Oncology; original-article; p38 Mitogen-Activated Protein Kinases - physiology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphorylation; Protein Biosynthesis - drug effects; Protein Kinases - physiology; Proto-Oncogene Proteins c-akt - physiology; Proto-Oncogene Proteins c-myc - antagonists & inhibitors; raf Kinases - physiology; Rapamycin; Signal transduction; Signal Transduction - drug effects; Sulfones - pharmacology; Sulfonylurea compounds; TOR protein; TOR Serine-Threonine Kinases; United States; mantle cell lymphoma; apoptosis; cell cycle; sulfonyl compounds; cytotoxicity
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2008.502

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.