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Please use this identifier to cite or link to this item: http://repository.li.mahidol.ac.th/dspace/handle/123456789/45259
Title: Inhibition of O-GlcNAcase sensitizes apoptosis and reverses bortezomib resistance in mantle cell lymphoma through modification of truncated bid
Authors: Sudjit Luanpitpong
Nawin Chanthra
Montira Janan
Jirarat Poohadsuan
Parinya Samart
Yaowalak U-Pratya
Yon Rojanasakul
Surapol Issaragrisil
West Virginia University
Mahidol University
Faculty of Medicine, Siriraj Hospital, Mahidol University
Wattanosoth Hospital
Keywords: Biochemistry, Genetics and Molecular Biology;Medicine
Issue Date: 1-Feb-2018
Citation: Molecular Cancer Therapeutics. Vol.17, No.2 (2018), 484-496
Abstract: © 2017 AACR. Aberrant energy metabolism represents a hallmark of cancer and contributes to numerous aggressive behaviors of cancer cells, including cell death and survival. Despite the poor prognosis of mantle cell lymphoma (MCL), due to the inevitable development of drug resistance, metabolic reprograming of MCL cells remains an unexplored area. Posttranslational modification of proteins via O-GlcNAcylation is an ideal sensor for nutritional changes mediated byO-GlcNAc transferase (OGT) and is removed byO-GlcNAcase (OGA). Using various small-molecule inhibitors of OGT and OGA, we found for the first time that O-GlcNAcylation potentiates MCL response to bortezomib. CRISPR interference of MGEA5 (encoding OGA) validated the apoptosis sensitization by OGlcNAcylation and OGA inhibition. To identify the potential clinical candidates, we tested MCL response to drug-like OGA inhibitor, ketoconazole, and verified that it exerts similar sensitizing effect on bortezomib-induced apoptosis. Investigations into the underlying molecular mechanisms reveal that bortezomib and ketoconazole act in concert to cause the accumulation of truncated Bid (tBid). Not only does ketoconazole potentiate tBid induction, but also increases tBid stability through O-GlcNAcylation that interferes with tBid ubiquitination and proteasomal degradation. Remarkably, ketoconazole strongly enhances bortezomib-induced apoptosis in de novo bortezomib-resistant MCL cells and in patient-derived primary cells with minimal cytotoxic effect on normal peripheral blood mononuclear cells and hepatocytes, suggesting its potential utility as a safe and effective adjuvant for MCL. Together, our findings provide novel evidence that combination of bortezomib and ketoconazole or other OGA inhibitors may present a promising strategy for the treatment of drug-resistant MCL.
URI: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85041462891&origin=inward
http://repository.li.mahidol.ac.th/dspace/handle/123456789/45259
ISSN: 15388514
15357163
Appears in Collections:Scopus 2018

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