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Review
. 2024 Jul 16;13(1):68.
doi: 10.1186/s40164-024-00529-z.

Versatile function of NF-ĸB in inflammation and cancer

Qiang Ma #  1 , Shuai Hao #  2   3 , Weilong Hong  2 , Vinay Tergaonkar  4 , Gautam Sethi  5 , Yu Tian  6 , Chenyang Duan  7
Affiliations
Review

Versatile function of NF-ĸB in inflammation and cancer

Qiang Ma et al. Exp Hematol Oncol. .

Abstract

Nuclear factor-kappaB (NF-ĸB) plays a crucial role in both innate and adaptive immune systems, significantly influencing various physiological processes such as cell proliferation, migration, differentiation, survival, and stemness. The function of NF-ĸB in cancer progression and response to chemotherapy has gained increasing attention. This review highlights the role of NF-ĸB in inflammation control, biological mechanisms, and therapeutic implications in cancer treatment. NF-ĸB is instrumental in altering the release of inflammatory factors such as TNF-α, IL-6, and IL-1β, which are key in the regulation of carcinogenesis. Specifically, in conditions including colitis, NF-ĸB upregulation can intensify inflammation, potentially leading to the development of colorectal cancer. Its pivotal role extends to regulating the tumor microenvironment, impacting components such as macrophages, fibroblasts, T cells, and natural killer cells. This regulation influences tumorigenesis and can dampen anti-tumor immune responses. Additionally, NF-ĸB modulates cell death mechanisms, notably by inhibiting apoptosis and ferroptosis. It also has a dual role in stimulating or suppressing autophagy in various cancers. Beyond these functions, NF-ĸB plays a role in controlling cancer stem cells, fostering angiogenesis, increasing metastatic potential through EMT induction, and reducing tumor cell sensitivity to chemotherapy and radiotherapy. Given its oncogenic capabilities, research has focused on natural products and small molecule compounds that can suppress NF-ĸB, offering promising avenues for cancer therapy.

Keywords: Cancer therapy; Inflammation; NF-ĸB; Small molecule inhibitors; Tumor microenvironment.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The survival and expression analysis of NF-ĸB in human cancers. A) Forest plot highlights the association between NF-ĸB and the overall survival of cancer patients. The upregulation of NF-ĸB has significant association with prognosis of glioma patients (poor prognosis); B) The Violin plot compares the expression of NF-ĸB in tumor and normal cells in different human cancers. (Created from TCGA database) (https://www.cancer.gov/ccg/research/genome-sequencing/tcga)
Fig. 2
Fig. 2
The NF-κB signaling in cells. There are two pathways for NF-κB, including canonical and non-canonical. In the canonical pathway, when there are stimuli such as TNF-α, IL-1β and LPS, the stimulation of NF-κB occurs through upregulation of TAK1 to increase the activity of IKKs for increasing proteasomal degradation of IkBα to further facilitate the nuclear transport of RelA and p53 for the regulation of genes. In the non-canonical pathway, the presence of LTβ, CD40L, and BAFF can stimulate it to promote proteasomal degradation of TRAF3 for stimulation of RelB and p52 transfer to the nucleus to regulate the expression level of genes (Created by Biorender.com)
Fig. 3
Fig. 3
NF-κB, inflammation, and cancer progression. Based on the evidence, NF-κB can cause inflammation to promote tumorigenesis, and in turn, inflammation can cause stimulation of NF-κB-mediated carcinogenesis. Therefore, there is a positive feedback loop between NF-κB and inflammation in the regulation of cancer progression. Moreover, the presence of exogenous insults such as bacterial infections and gut microflora can stimulate the TLR4 receptor to induce the NF-κB axis. The non-canonical pathway of NF-κB also interacts with BCL-3 in promoting cancer progression. Moreover, when TRIM14 is induced, it suppresses the degradation of p100/p52 by autophagy to maintain the function of NF-κB in cancer progression (Created by Biorender.com)
Fig. 4
Fig. 4
The NF-ĸB axis and tumor microenvironment components. The TAMs and CAFs are primary regulators of cancer progression through interaction with NF-ĸB. The secretion of IL-8 from CAFs can induce NF-ĸB to increase DNA damage repair and radioresistance. Moreover, activated NF-ĸB forces CAFs to secrete IL-6 for stimulation of the STAT3/osteopontin axis, causing NF-ĸB upregulation and acceleration in the metastasis and proliferation of cancer cells. The upregulation of NF-ĸB by Mincle and Tap73 can enhance the recruitment and M2 polarization of macrophages. Moreover, NF-ĸB downregulation by DRD2 increases M1 polarization of macrophages to secrete exosomes for inhibition of NF-ĸB. The secretion of CSF1 and CXCL1 as a result of NF-ĸB activation can cause immunosuppression. NF-ĸB promotes the recruitment of CD8 + T cells and MHC-I antigen presentation. Moreover, TLR1 upregulation activates NF-ĸB to release IFN-γ in the stimulation of NK cells. Finally, IRF1 upregulation by NF-ĸB can increase anti-cancer immunity. Moreover, NF-ĸB accelerates the release of IL-10 from DC cells to affect cancer progression (Created by Biorender.com)
Fig. 5
Fig. 5
The NF-κB interaction with other biological mechanisms. The interesting part is the induction of apoptosis by NF-κB when the ROS levels in the mitochondria increase. Moreover, NF-κB promotes levels of VEGF to induce angiogenesis. The upregulation of SLC7A11 by NF-κB can disrupt ferroptosis. Furthermore, GLUT3 upregulation by NF-κB increases the glucose uptake in cancer cells to induce glycolysis. The interaction of autophagy and NF-κB is mutual, and in addition to NF-κB function in the regulation of autophagy, the autophagy mechanisms can also regulate NF-κB by degradation of related proteins (Created by Biorender.com)
Fig. 6
Fig. 6
The involvement of NF-κB axis in the proliferation and invasion of cancer. NF-κB increases both proliferation and metastasis after transfer into the nucleus. CYS1 interacts with RPS27A to develop CYS1/RPS27A complex. Then, this complex promotes p65 expression and its nuclear transfer to enhance the proliferation. Moreover, IFNα promotes IFITM1 expression to facilitate the proliferation of cancer. The upregulation of MMP9 induced by the Akt/NF-κB axis can enhance the metastasis and invasion of cancer. Furthermore, TNF-α stimulates IKK through the upregulation of PI3K/Akt/mTOR to mediate the NF-κB axis. At the next step, NF-κB promotes HIF-1α expression to facilitate proliferation and invasion of cancer cells (Created by Biorender.com)
Fig. 7
Fig. 7
The NF-κB axis participates in the development of chemoresistance and radioresistance in cancer. The stimulation of EGFR triggers the ERK/Akt axis to mediate the nuclear transfer of NF-κB. Then, NF-κB increases P-gp expression to induce drug resistance. Furthermore, SREBP1 stimulates NF-κB to prevent apoptosis in the development of drug resistance, while the SREBP1/NF-κB axis is disrupted by fatostatin. Moreover, HDAC5 positively interacts with NF-κB to increase LSD1 expression in sorafenib resistance. The exposure of cancer cells to irradiation increases IKK expression to mediate β1-integrin expression through the nuclear transfer of the p50/p65 complex to induce radioresistance (Created by Biorender.com)
Fig. 8
Fig. 8
The NF-κB regulation by non-coding RNAs in cancer. Although the studies have highlighted the role of these RNA molecules in NF-κB control, there is another side which is the regulation of RNAs by NF-κB such as an increase in miR-574 expression by NF-κB (Created by Biorender.com)
Fig. 9
Fig. 9
The small molecule inhibitors of NF-κB (Created by Biorender.com)
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