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

Oncogene volume 28, pages 1518–1528 (2009)Cite this article

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.

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Acknowledgements

This work was supported by a charitable contribution from Mr and Mrs Henryk and Rochelle Schwarz and SBIR grant # 1 R43 CA134108-01A1. E Premkumar Reddy was supported by grant CA109820. Disclosure: Dr Groopman is a consultant to Onconova Therapeutics, Inc.

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Authors and Affiliations

  1. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    A Prasad, I-W Park, H Allen, X Zhang & J E Groopman

  2. Department of Biochemistry, Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA, USA

    M V R Reddy, R Boominathan & E P Reddy

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  1. A Prasad
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Correspondence to J E Groopman.

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Prasad, A., Park, IW., Allen, H. et al. Styryl sulfonyl compounds inhibit translation of cyclin D1 in mantle cell lymphoma cells. Oncogene 28, 1518–1528 (2009). https://doi.org/10.1038/onc.2008.502

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