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Title: Sustained activation of non-canonical NF-κB signalling drives glycolytic reprogramming in doxorubicin-resistant DLBCL
Authors: Lim, Shen Kiat
Peng, Chen Chen
Low, Shannon
Vijay, Varsheni
Budiman, Andrea
Phang, Beng Hooi
Lim, Jing Quan
Jeyasekharan, Anand D.
Lim, Soon Thye
Ong, Choon Kiat
Tan, Suet Mien
Li, Yinghui
Keywords: Science::Biological sciences
Issue Date: 2022
Source: Lim, S. K., Peng, C. C., Low, S., Vijay, V., Budiman, A., Phang, B. H., Lim, J. Q., Jeyasekharan, A. D., Lim, S. T., Ong, C. K., Tan, S. M. & Li, Y. (2022). Sustained activation of non-canonical NF-κB signalling drives glycolytic reprogramming in doxorubicin-resistant DLBCL. Leukemia.
Project: NRFNRFF2018-04
Journal: Leukemia
Abstract: DLBCL is the most common lymphoma with high tumor heterogeneity. Treatment refractoriness and relapse from R-CHOP therapy in patients remain a clinical problem. Activation of the non-canonical NF-κB pathway is associated with R-CHOP resistance. However, downstream targets of non-canonical NF-κB mediating R-CHOP-induced resistance remains uncharacterized. Here, we identify the common mechanisms underlying both intrinsic and acquired resistance that are induced by doxorubicin, the main cytotoxic component of R-CHOP. We performed global transcriptomic analysis of (1) a panel of resistant versus sensitive and (2) isogenic acquired doxorubicin-resistant DLBCL cell lines following short and chronic exposure to doxorubicin respectively. Doxorubicin-induced stress in resistant cells activates a distinct transcriptional signature that is enriched in metabolic reprogramming and oncogenic signalling. Selective and sustained activation of non-canonical NF-κB signalling in these resistant cells exacerbated their survival by augmenting glycolysis. In response to doxorubicin, p52-RelB complexes transcriptionally activated multiple glycolytic regulators with prognostic significance through increased recruitment at their gene promoters. Targeting p52-RelB and their targets in resistant cells increased doxorubicin sensitivity in vitro and in vivo. Collectively, our study uncovered novel molecular drivers of doxorubicin-induced resistance that are regulated by non-canonical NF-κB pathway. We reveal new avenues of therapeutic targeting for R-CHOP-treated refractory/relapsed DLBCL patients.
ISSN: 0887-6924
DOI: 10.1038/s41375-022-01769-w
Schools: School of Biological Sciences 
Organisations: Institute of Molecular and Cell Biology, A*STAR
Rights: © 2022 The Author(s), under exclusive licence to Springer Nature Limited. All rights reserved. This version of the article has been accepted for publication, after peer review and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at:
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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