NF-κB transcription factor induces drug resistance through MDR1 expression in cancer cells

Bentires‐Alj, Mohamed; Barbu, Véronique; Fillet, Marianne; Chariot, Alain; Relić, Biserka; Jacobs, Nathalie; Gielen, Jacques; Merville, Marie‐Paule; Bours, Vincent

doi:10.1038/sj.onc.1206056

Cited by 405 publications

(287 citation statements)

References 54 publications

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“…Because the anti-apoptotic activity of NF-κB in tumors contributes to their chemo-or radio-resistance, NF-κB inhibition enhances apoptotic response to chemotherapy [61,151] and radiotherapy [132,161]. In addition, recent studies have identified a consensus NF-κB binding site in the human multidrug resistance gene 1 (MDR1), and found that in vitro, NF-κB transactivates the expression of MDR1, further supporting the role of NF-κB in chemoresistance [10]. However, NF-κB has also been suggested to be required for paclitaxel-induced cell death [53].…”

Section: Nf-κb and Chemo-/radio-resistancementioning

confidence: 98%

NF‐κB as a potential molecular target for cancer therapy

et al. 2007

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Abstract. Nuclear factor κB (NF-κB), a transcription factor, plays an important role in carcinogenesis as well as in the regulation of immune and inflammatory responses. NF-κB induces the expression of diverse target genes that promote cell proliferation, regulate apoptosis, facilitate angiogenesis and stimulate invasion and metastasis. Furthermore, many cancer cells show aberrant or constitutive NF-κB activation which mediates resistance to chemo-and radio-therapy. Therefore, the inhibition of NF-κB activation and its signaling pathway offers a potential cancer therapy strategy. In addition, recent studies have shown that NF-κB can also play a tumor suppressor role in certain settings. In this review, we focus on the role of NF-κB in carcinogenesis and the therapeutic potential of targeting NF-κB in cancer therapy.Keywords: NF-κB, NF-κB inhibitor, carcinogenesis, cancer therapy Structure, function and regulation of NF-κBNuclear factor-κB (NF-κB) was first identified in 1986 as a transcription factor that binds to a 10 bp DNA element in kappa immunoglobulin light-chain enhancer in B cells [128]. The mammalian NF-κB family consists of 5 members: NF-κB1 (p50/p105), NF-κB2 (p52/p100), c-Rel, RelA (p65) and RelB (Fig. 1). RelA, c-Rel and RelB are synthesized in their mature forms and contain a transactivation domain that interacts with the transcriptional apparatus. On the other hand, NF-κB1 (p50/p105) and NF-κB2 (p52/p100) are synthesized in precursor forms (p100 and p105) which contain C-terminal ankyrin repeats that are proteolysed by the proteasome resulting in the production of mature proteins (p50 and p52). Both p50 and p52 contain a DNA binding domain but lack a transactivation domain. NF-κB proteins exist in unstimulated cells as homo-or heterodimers bound to IκB proteins. Whereas RelB forms only heterodimers, all the other proteins can form both homo-and heterodimers. NF-κB proteins are characterized by the presence of a highly conserved 300 amino acid Rel homology domain that is located toward the N terminus of the protein, and which is responsible for DNA binding, dimerization, and interaction with specific inhibitory factors known as IκB proteins [7,36].

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Section: Nf-κb and Chemo-/radio-resistancementioning

confidence: 98%

NF‐κB as a potential molecular target for cancer therapy

et al. 2007

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“…NF-kB activation as a mechanism for resistance to EGFR inhibitors NF-kB-activating cascades promote resistance to chemotherapy through multiple mechanisms, including the transcriptional induction of multidrug resistance gene-1 (MDR1) in colon cancer cells [45]. Recent studies have also defined mechanisms by which resistance occurs through crosstalk between EGFR-and NF-kB-dependent pathways.…”

Section: Trends In Molecular Medicinementioning

confidence: 99%

EGFR and NF-κB: partners in cancer

Shostak

Chariot

2015

Trends in Molecular Medicine

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“…NF-kB also enhances the expression of mdr1, whose product, P-glycoprotein (P-gp), a plasma membrane transporter, mediates chemoresistance by inducing the efflux of chemotherapeutic molecules, explaining its broad impact, not only in oncogenic transformation but also in chemoresistance. 2 NF-kB consists of a family of Rel-domain-containing proteins including Rel A (p65), Rel B, c-Rel, p50 (NF-kB1), and p52 (NFkB2). 3,4 Phosphorylation-dependent cleavage of inactive p100 yields active p52, while cleavage of p105 yields p50.…”

Section: Introductionmentioning

confidence: 99%

Targeting NF-κB in hematologic malignancies

et al. 2006

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The transcription factor nuclear factor kappa B (NF-jB) can intervene in oncogenesis by virtue of its capacity to regulate the expression of a plethora of genes that modulate apoptosis, and cell survival as well as proliferation, inflammation, tumor metastasis and angiogenesis. Different reports demonstrate the intrinsic activation of NF-jB in lymphoid and myeloid malignancies, including preneoplastic conditions such as myelodysplastic syndromes, underscoring its implication in malignant transformation. Targeting intrinsic NF-jB activation, as well as its upstream and downstream regulators, may hence constitute an additional approach to the oncologist's armamentarium. Several small inhibitors of the NF-jB-activatory kinase IjB kinase, of the proteaseome, or of the DNA binding of NF-jB subunits are under intensive investigation. Currently used cytotoxic agents can induce NF-jB activation as an unwarranted side effect, which confers apoptosis suppression and hence resistance to these drugs. Thus, NF-jB inhibitory molecules may be clinically useful, either as single therapeutic agents or in combination with classical chemotherapeutic agents, for the treatment of hematological malignancies.

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NF-κB transcription factor induces drug resistance through MDR1 expression in cancer cells

Cited by 405 publications

References 54 publications

NF‐κB as a potential molecular target for cancer therapy

NF‐κB as a potential molecular target for cancer therapy

EGFR and NF-κB: partners in cancer

Targeting NF-κB in hematologic malignancies

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