Sustained activation of non-canonical NF-κB signalling drives glycolytic reprogramming in doxorubicin-resistant DLBCL

Lim, Sai‐Kiang; 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

doi:10.1038/s41375-022-01769-w

Cited by 17 publications

(10 citation statements)

References 48 publications

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“…Elevated RelB activity reported in a new subset of DLBCL patients is found to confer resistance to DNA damage-induced apoptosis along with increased cIAP2 expression [113]. In a more recent finding, sustained activation of the non-canonical NF-κB signalling is also shown to drive doxorubicin resistance in DLBCL via enhanced glycolysis [215]. Hence, these studies indicate the existence of a high degree of NF-κB dysregulation in cancer.…”

Section: Aberrant Nf-κb Activation Driven Expression Of Tumour Promot...mentioning

confidence: 74%

Transcriptional Regulation during Aberrant Activation of NF-κB Signalling in Cancer

Deka

2023

Cells

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The NF-κB signalling pathway is a major signalling cascade involved in the regulation of inflammation and innate immunity. It is also increasingly recognised as a crucial player in many steps of cancer initiation and progression. The five members of the NF-κB family of transcription factors are activated through two major signalling pathways, the canonical and non-canonical pathways. The canonical NF-κB pathway is prevalently activated in various human malignancies as well as inflammation-related disease conditions. Meanwhile, the significance of non-canonical NF-κB pathway in disease pathogenesis is also increasingly recognized in recent studies. In this review, we discuss the double-edged role of the NF-κB pathway in inflammation and cancer, which depends on the severity and extent of the inflammatory response. We also discuss the intrinsic factors, including selected driver mutations, and extrinsic factors, such as tumour microenvironment and epigenetic modifiers, driving aberrant activation of NF-κB in multiple cancer types. We further provide insights into the importance of the interaction of NF-κB pathway components with various macromolecules to its role in transcriptional regulation in cancer. Finally, we provide a perspective on the potential role of aberrant NF-κB activation in altering the chromatin landscape to support oncogenic development.

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Section: Aberrant Nf-κb Activation Driven Expression Of Tumour Promot...mentioning

confidence: 74%

Transcriptional Regulation during Aberrant Activation of NF-κB Signalling in Cancer

Deka

2023

Cells

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“…Cancers Proliferation Induce the expression of cyclins and proto-oncogenes 252 – 256 , 615 , 616 Apoptosis Depend on the balance between apoptotic and survival proteins 258 – 262 Angiogenesis Upregulation of proangiogenic factors 263 , 264 , 266 – 273 , 617 Metastasis Promote EMT, facilitate cancer extravasation and colonization 276 – 282 Immune evasion Foster an immunosuppressive TME 243 , 262 , 283 , 284 Metabolic reprogramming Remodeling of cellular metabolism, facilitate metabolic adaptation to nutrient deprivation. 189 , 197 – 200 , 286 – 291 Drug resistance Regulate pro- and anti-apoptotic factors, metabolic reprogramming, gut microbiota, gene mutation 191 , 292 , 294 , 295 , 297 – 301 B. Inflammation and autoimmune diseases Rheumatoid arthritis Promotes the proliferation of FLS, activation of immune cells, cytokine production 313 – 318 Osteoarthritis Cartilage destruction, chondrocyte apoptosis 325 – 328 Multiple sclerosi...…”

Section: Nf-κb Signaling In Human Diseasesmentioning

confidence: 99%

“…Targeting p52-RelB increased sensitivity to doxorubicin. 294 The gut microbiota may be involved in chemotherapy resistance in malignant tumors. It has been found in a study that enrichment of Mycobacterium avium upregulated intratumoral LPS, which subsequently promoted prostate cancer progression and docetaxel resistance through activation of the NF-κB-IL6-STAT3 signaling axis.…”

Section: Nf-κb Signaling In Human Diseasesmentioning

confidence: 99%

NF-κB in biology and targeted therapy: new insights and translational implications

Guo,

Jin,

Chen

et al. 2024

Sig Transduct Target Ther

172

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NF-κB signaling has been discovered for nearly 40 years. Initially, NF-κB signaling was identified as a pivotal pathway in mediating inflammatory responses. However, with extensive and in-depth investigations, researchers have discovered that its role can be expanded to a variety of signaling mechanisms, biological processes, human diseases, and treatment options. In this review, we first scrutinize the research process of NF-κB signaling, and summarize the composition, activation, and regulatory mechanism of NF-κB signaling. We investigate the interaction of NF-κB signaling with other important pathways, including PI3K/AKT, MAPK, JAK-STAT, TGF-β, Wnt, Notch, Hedgehog, and TLR signaling. The physiological and pathological states of NF-κB signaling, as well as its intricate involvement in inflammation, immune regulation, and tumor microenvironment, are also explicated. Additionally, we illustrate how NF-κB signaling is involved in a variety of human diseases, including cancers, inflammatory and autoimmune diseases, cardiovascular diseases, metabolic diseases, neurological diseases, and COVID-19. Further, we discuss the therapeutic approaches targeting NF-κB signaling, including IKK inhibitors, monoclonal antibodies, proteasome inhibitors, nuclear translocation inhibitors, DNA binding inhibitors, TKIs, non-coding RNAs, immunotherapy, and CAR-T. Finally, we provide an outlook for research in the field of NF-κB signaling. We hope to present a stereoscopic, comprehensive NF-κB signaling that will inform future research and clinical practice.

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“…The GCB-DLBCL subtype exhibits a better prognosis than the ABC subtype, and recently, genetic aberrations have been integrated into the cell of origin (COO) classification [ 4 , 5 , 6 ]. Over 30% of DLBCL patients experience recurrent or progressive disease after R-CHOP treatment [ 4 , 7 , 8 , 9 ]. Therefore, there is a need for novel therapeutic strategies that target signaling pathways to improve DLBCL therapies.…”

Section: Introductionmentioning

confidence: 99%

High G9a Expression in DLBCL and Its Inhibition by Niclosamide to Induce Autophagy as a Therapeutic Approach

Hsu,

Chang,

Chuang

et al. 2023

Cancers

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Background: Diffuse large B-cell lymphoma (DLBCL) is a malignant lymphoid tumor disease that is characterized by heterogeneity, but current treatment does not benefit all patients, which highlights the need to identify oncogenic genes and appropriate drugs. G9a is a histone methyltransferase that catalyzes histone H3 lysine 9 (H3K9) methylation to regulate gene function and expression in various cancers. Methods: TCGA and GTEx data were analyzed using the GEPIA2 platform. Cell viability under drug treatment was assessed using Alamar Blue reagent; the interaction between G9a and niclosamide was assessed using molecular docking analysis; mRNA and protein expression were quantified in DLBCL cell lines. Finally, G9a expression was quantified in 39 DLBCL patient samples. Results: The TCGA database analysis revealed higher G9a mRNA expression in DLBCL compared to normal tissues. Niclosamide inhibited DLBCL cell line proliferation in a time- and dose-dependent manner, reducing G9a expression and increasing p62, BECN1, and LC3 gene expression by autophagy pathway regulation. There was a correlation between G9a expression in DLBCL samples and clinical data, showing that advanced cancer stages exhibited a higher proportion of G9a-expressing cells. Conclusion: G9a overexpression is associated with tumor progression in DLBCL. Niclosamide effectively inhibits DLBCL growth by reducing G9a expression via the cellular autophagy pathway; therefore, G9a is a potential molecular target for the development of therapeutic strategies for DLBCL.

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Sustained activation of non-canonical NF-κB signalling drives glycolytic reprogramming in doxorubicin-resistant DLBCL

Cited by 17 publications

References 48 publications

Transcriptional Regulation during Aberrant Activation of NF-κB Signalling in Cancer

Transcriptional Regulation during Aberrant Activation of NF-κB Signalling in Cancer

NF-κB in biology and targeted therapy: new insights and translational implications

High G9a Expression in DLBCL and Its Inhibition by Niclosamide to Induce Autophagy as a Therapeutic Approach

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