NF-κB: A Druggable Target in Acute Myeloid Leukemia

Francesco, Barbara Di; Verzella, Daniela; Capece, Daria; Vecchiotti, Davide; Nolfi, Mauro Di Vito; Flati, Irene; Cornice, Jessica; Padova, Monica Di; Angelucci, Adriano; Alesse, Edoardo; Zazzeroni, Francesca

doi:10.3390/cancers14143557

Cited by 22 publications

(20 citation statements)

References 196 publications

(254 reference statements)

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“…STAT3 and STAT6 are also known to be activated during inflammation in the tumor microenvironment; their activity may be associated with an increased inflammatory response during leukemia progression [ 35 , 36 , 37 ]. It has been posited that NF-kB plays a role in the formation of a leukemic microenvironment during the stimulation of a chronic inflammation in the BM niche under the effect of the cytokine tumor necrosis factor-α (TNFα), which supports a favorable environment for the survival and production of leukemic cells [ 38 , 39 , 40 ].…”

Section: Resultsmentioning

confidence: 99%

Studying Signaling Pathway Activation in TRAIL-Resistant Macrophage-Like Acute Myeloid Leukemia Cells

Lomovskaya,

Krasnov,

Kobyakova

et al. 2024

Acta Naturae

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Acute myeloid leukemia (AML) is a malignant neoplasm characterized by extremely low curability and survival. The inflammatory microenvironment and maturation (differentiation) of AML cells induced by it contribute to the evasion of these cells from effectors of antitumor immunity. One of the key molecular effectors of immune surveillance, the cytokine TRAIL, is considered a promising platform for developing selective anticancer drugs. Previously, under in vitro conditions of the inflammatory microenvironment (a three-dimensional high-density culture of THP-1 AML cells), we demonstrated the emergence of differentiated macrophage-like THP-1ad clones resistant to TRAIL-induced death. In the present study, constitutive activation of proinflammatory signaling pathways, associated transcription factors, and increased expression of the anti-apoptotic BIRC3 gene were observed in TRAIL-resistant macrophage-like THP-1ad AML cells. For the first time, a bioinformatic analysis of the transcriptome revealed the main regulator, the IL1B gene, which triggers proinflammatory activation and induces resistance to TRAIL in THP–1ad macrophage-like cells.

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Section: Resultsmentioning

confidence: 99%

Studying Signaling Pathway Activation in TRAIL-Resistant Macrophage-Like Acute Myeloid Leukemia Cells

Lomovskaya,

Krasnov,

Kobyakova

et al. 2024

Acta Naturae

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“…TNF signaling is also linked to NF-kB signaling. Although NF-kB signaling pathway has been mainly associated with a survival response in cancer to protect cells from apoptosis [60] different drugs targeting this cascade have been developed to control cancer cell proliferation [61]. Dual functions of NF-kB signaling appear to result from the ability of these transcription factors to either activate or repress transcription of genes depending on interaction with transcription co-activator or repressors and post-translational modifications [62, 63].…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profiling Unveils the Temporal Dynamics of CIGB-300-Regulated Transcriptome in AML Cells

Vázquez-Blomquist

Ramón

Rosales

et al. 2023

Preprint

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Protein kinase CK2 activity is implicated in the pathogenesis of various hematological malignancies like Acute Myeloid Leukemia (AML) that remains challenging concerning treatment. Consequently, here we used Illumina HT-12 microarray gene RNA expression profiling to study the molecular events that might support the anti-leukemic effect of CIGB-300 peptide which targets both CK2 substrates and the CK2α catalytic subunits on HL-60 and OCI-AML3 cell lines. As a result, 185 and 812 genes appeared significantly modulated in HL-60 cells at 30 min and 3 h of incubation with CIGB-300 for p< 0.01 and FC>│1.5│, respectively; while 222 and 332 genes appeared modulated in OCI-AML3 cells. Importantly, functional enrichment analysis evidenced that genes and transcription factors related to apoptosis, cell cycle, leukocyte differentiation, signaling by cytokines/interleukins, and NF-kB, TNF signaling pathways were significantly represented in AML cells transcriptomic profiles. The influence of CIGB-300 on these biological processes and pathways is dependent on the cellular background, in first place, and treatment duration. Of note, the impact of the peptide on NF-kB signaling was corroborated by the quantification of selected NF-kB target genes, as well as the measurement of p50 binding activity and soluble TNF-α induction. Quantification of CSF1/M-CSF and CDKN1A/P21 by PCR supports peptide effects on differentiation and cell cycle. Overall, here we explore for the first time the temporal dynamics of the gene expression profile regulated by CIGB-300 and provide fresh molecular clues concerning the antineoplastic effect of CIGB-300 in two relevant AML backgrounds.

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“…In AML, NFκB transcriptional activity plays an established role in fostering tumor progression through paracrine secretion of cytokines in the microenvironment. However, the constitutive activation of NFκB, attributed to aberrant feedback, is associated with diverse advantages for AML cells, especially for leukemia stem cells [ 99 , 100 , 101 ]. This makes NFκB-activating modules, such as stalled, substrate-bound OGG1, a very strong candidate intervention target in AML.…”

Section: Oxidative Stress As a Driver For Cancer Plasticitymentioning

confidence: 99%

OGG1 as an Epigenetic Reader Affects NFκB: What This Means for Cancer

Vlahopoulos,

Pan,

Varisli

et al. 2023

Cancers

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8-oxoguanine glycosylase 1 (OGG1), which was initially identified as the enzyme that catalyzes the first step in the DNA base excision repair pathway, is now also recognized as a modulator of gene expression. What is important for cancer is that OGG1 acts as a modulator of NFκB-driven gene expression. Specifically, oxidant stress in the cell transiently halts enzymatic activity of substrate-bound OGG1. The stalled OGG1 facilitates DNA binding of transactivators, such as NFκB to their cognate sites, enabling the expression of cytokines and chemokines, with ensuing recruitment of inflammatory cells. Recently, we highlighted chief aspects of OGG1 involvement in regulation of gene expression, which hold significance in lung cancer development. However, OGG1 has also been implicated in the molecular underpinning of acute myeloid leukemia. This review analyzes and discusses how these cells adapt through redox-modulated intricate connections, via interaction of OGG1 with NFκB, which provides malignant cells with alternative molecular pathways to transform their microenvironment, enabling adjustment, promoting cell proliferation, metastasis, and evading killing by therapeutic agents.

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NF-κB: A Druggable Target in Acute Myeloid Leukemia

Cited by 22 publications

References 196 publications

Studying Signaling Pathway Activation in TRAIL-Resistant Macrophage-Like Acute Myeloid Leukemia Cells

Studying Signaling Pathway Activation in TRAIL-Resistant Macrophage-Like Acute Myeloid Leukemia Cells

Gene Expression Profiling Unveils the Temporal Dynamics of CIGB-300-Regulated Transcriptome in AML Cells

OGG1 as an Epigenetic Reader Affects NFκB: What This Means for Cancer

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