Sustained activation of non-canonical NF-κB signalling drives glycolytic reprogramming in doxorubicin-resistant DLBCL
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 medi...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2023
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| Online Access: | https://hdl.handle.net/10356/164468 |
| _version_ | 1811691017006481408 |
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| author | 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 |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences 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 |
| author_sort | Lim, Shen Kiat |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T06:13:12Z |
| format | Journal Article |
| id | ntu-10356/164468 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:13:12Z |
| publishDate | 2023 |
| record_format | dspace |
| spelling | ntu-10356/1644682023-02-28T17:13:32Z Sustained activation of non-canonical NF-κB signalling drives glycolytic reprogramming in doxorubicin-resistant DLBCL 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 School of Biological Sciences Institute of Molecular and Cell Biology, A*STAR Science::Biological sciences Cell Signalling Non-Hodgkin Lymphoma 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. Nanyang Technological University National Medical Research Council (NMRC) National Research Foundation (NRF) Submitted/Accepted version This study is funded by the National Research Foundation (NRF) Singapore, under its Singapore NRF Fellowship (NRFNRFF2018-04). In addition, we thank the Nanyang Assistant Professorship (NAP) Startup-grant to Y.L. lab and National Medical Research Council (NMRC-OFLCG18May0028), Tanoto Foundation and Ling Foundation for their support. 2023-01-27T02:21:12Z 2023-01-27T02:21:12Z 2022 Journal Article 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. https://dx.doi.org/10.1038/s41375-022-01769-w 0887-6924 https://hdl.handle.net/10356/164468 10.1038/s41375-022-01769-w 36446947 2-s2.0-85142927402 en NRFNRFF2018-04 NMRC-OFLCG18May0028 NTU-SUG Leukemia © 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: http://dx.doi.org/10.1038/s41375-022-01769-w. application/pdf application/pdf |
| spellingShingle | Science::Biological sciences Cell Signalling Non-Hodgkin Lymphoma 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 Sustained activation of non-canonical NF-κB signalling drives glycolytic reprogramming in doxorubicin-resistant DLBCL |
| title | Sustained activation of non-canonical NF-κB signalling drives glycolytic reprogramming in doxorubicin-resistant DLBCL |
| title_full | Sustained activation of non-canonical NF-κB signalling drives glycolytic reprogramming in doxorubicin-resistant DLBCL |
| title_fullStr | Sustained activation of non-canonical NF-κB signalling drives glycolytic reprogramming in doxorubicin-resistant DLBCL |
| title_full_unstemmed | Sustained activation of non-canonical NF-κB signalling drives glycolytic reprogramming in doxorubicin-resistant DLBCL |
| title_short | Sustained activation of non-canonical NF-κB signalling drives glycolytic reprogramming in doxorubicin-resistant DLBCL |
| title_sort | sustained activation of non canonical nf κb signalling drives glycolytic reprogramming in doxorubicin resistant dlbcl |
| topic | Science::Biological sciences Cell Signalling Non-Hodgkin Lymphoma |
| url | https://hdl.handle.net/10356/164468 |
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