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

Publication ,  Journal Article
Pham, LV; Bryant, JL; Mendez, R; Chen, J; Tamayo, AT; Xu-Monette, ZY; Young, KH; Manyam, GC; Yang, D; Medeiros, LJ; Ford, RJ
Published in: Oncotarget
December 6, 2016

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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Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

December 6, 2016

Volume

7

Issue

49

Start / End Page

80599 / 80611

Location

United States

Related Subject Headings

  • Transfection
  • Signal Transduction
  • RNAi Therapeutics
  • RNA, Messenger
  • RNA Interference
  • Organotechnetium Compounds
  • NFATC Transcription Factors
  • NF-kappa B
  • N-Acetylglucosaminyltransferases
  • Mice, SCID
 

Citation

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MLA
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Pham, L. V., Bryant, J. L., Mendez, R., Chen, J., Tamayo, A. T., Xu-Monette, Z. Y., … Ford, R. J. (2016). Targeting the hexosamine biosynthetic pathway and O-linked N-acetylglucosamine cycling for therapeutic and imaging capabilities in diffuse large B-cell lymphoma. Oncotarget, 7(49), 80599–80611. https://doi.org/10.18632/oncotarget.12413
Pham, Lan V., Jerry L. Bryant, Richard Mendez, Juan Chen, Archito T. Tamayo, Zijun Y. Xu-Monette, Ken H. Young, et al. “Targeting the hexosamine biosynthetic pathway and O-linked N-acetylglucosamine cycling for therapeutic and imaging capabilities in diffuse large B-cell lymphoma.Oncotarget 7, no. 49 (December 6, 2016): 80599–611. https://doi.org/10.18632/oncotarget.12413.
Pham LV, Bryant JL, Mendez R, Chen J, Tamayo AT, Xu-Monette ZY, et al. Targeting the hexosamine biosynthetic pathway and O-linked N-acetylglucosamine cycling for therapeutic and imaging capabilities in diffuse large B-cell lymphoma. Oncotarget. 2016 Dec 6;7(49):80599–611.
Pham, Lan V., et al. “Targeting the hexosamine biosynthetic pathway and O-linked N-acetylglucosamine cycling for therapeutic and imaging capabilities in diffuse large B-cell lymphoma.Oncotarget, vol. 7, no. 49, Dec. 2016, pp. 80599–611. Pubmed, doi:10.18632/oncotarget.12413.
Pham LV, Bryant JL, Mendez R, Chen J, Tamayo AT, Xu-Monette ZY, Young KH, Manyam GC, Yang D, Medeiros LJ, Ford RJ. Targeting the hexosamine biosynthetic pathway and O-linked N-acetylglucosamine cycling for therapeutic and imaging capabilities in diffuse large B-cell lymphoma. Oncotarget. 2016 Dec 6;7(49):80599–80611.

Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

December 6, 2016

Volume

7

Issue

49

Start / End Page

80599 / 80611

Location

United States

Related Subject Headings

  • Transfection
  • Signal Transduction
  • RNAi Therapeutics
  • RNA, Messenger
  • RNA Interference
  • Organotechnetium Compounds
  • NFATC Transcription Factors
  • NF-kappa B
  • N-Acetylglucosaminyltransferases
  • Mice, SCID