Oncotarget

Research Papers:

Targeting the hexosamine biosynthetic pathway and O-linked N-acetylglucosamine cycling for therapeutic and imaging capabilities in diffuse large B-cell lymphoma

Lan V. Pham _, Jerry L. Bryant, Richard Mendez, Juan Chen, Archito T. Tamayo, Zijun Y. Xu-Monette, Ken H. Young, Ganiraju C. Manyam, David Yang, David Yang, L. Jeffrey Medeiros and Richard J. Ford

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Oncotarget. 2016; 7:80599-80611. https://doi.org/10.18632/oncotarget.12413

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Abstract

Lan V. Pham1, Jerry L. Bryant2, Richard Mendez1, Juan Chen1, Archito T. Tamayo1, Zijun Y. Xu-Monette1, Ken H. Young1, Ganiraju C. Manyam3, David Yang2, L. Jeffrey Medeiros1, Richard J. Ford1

1Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

2Division of Translational Medicine, Cell>Point Pharmaceuticals, Centennial, CO, USA

3Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Correspondence to:

Lan V. Pham, email: [email protected]

Keywords: DLBCL, hexosamine, NF-κB, NFAT, O-linked N-acetylglucosamine

Received: March 23, 2016     Accepted: September 19, 2016     Published: October 03, 2016

ABSTRACT

The hexosamine biosynthetic pathway (HBP) requires two key nutrients glucose and glutamine for O-linked N-acetylglucosamine (O-GlcNAc) cycling, a post-translational protein modification that adds GlcNAc to nuclear and cytoplasmic proteins. Increased GlcNAc has been linked to regulatory factors involved in cancer cell growth and survival. However, the biological significance of GlcNAc in diffuse large B-cell lymphoma (DLBCL) is not well defined. This study is the first to show that both the substrate and the endpoint O-GlcNAc transferase (OGT) enzyme of the HBP were highly expressed in DLBCL cell lines and in patient tumors compared with normal B-lymphocytes. Notably, high OGT mRNA levels were associated with poor survival of DLBCL patients. Targeting OGT via small interference RNA in DLBCL cells inhibited activation of GlcNAc, nuclear factor kappa B (NF-κB), and nuclear factor of activated T-cells 1 (NFATc1), as well as cell growth. Depleting both glucose and glutamine in DLBCL cells or treating them with an HBP inhibitor (azaserine) diminished O-GlcNAc protein substrate, inhibited constitutive NF-κB and NFATc1 activation, and induced G0/G1 cell-cycle arrest and apoptosis. Replenishing glucose-and glutamine-deprived DLBCL cells with a synthetic glucose analog (ethylenedicysteine-N-acetylglucosamine [ECG]) reversed these phenotypes. Finally, we showed in both in vitro and in vivo murine models that DLBCL cells easily take up radiolabeled technetium-99m-ECG conjugate. These findings suggest that targeting the HBP has therapeutic relevance for DLBCL and underscores the imaging potential of the glucosamine analog ECG in DLBCL.


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