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MINI REVIEW
Year : 2017  |  Volume : 3  |  Issue : 5  |  Page : 181-184

The significance of nuclear factor-kappa B signaling pathway in glioma: A review


1 Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
2 Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

Date of Submission10-Oct-2016
Date of Acceptance17-Mar-2017
Date of Web Publication26-Oct-2017

Correspondence Address:
Yanyang Tu
Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Xi'an 710038, Shaanxi
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ctm.ctm_48_16

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  Abstract 

In recent years, the research on the regulation of nuclear factor kappa B (NF-κB) signaling pathway in tumor cell apoptosis and proliferation is a hot topic. It has been reported that activated NF-κB pathway exerts antiapoptotic effect by inducing antiapoptotic and cell proliferation-related target gene expression, including the Bcl-2 family, survivin, COX-2, Cyclin Dl, and epidermal growth factor receptor, eventually leading to accelerated cell cycle progression and enhanced antiapoptotic and proliferation ability of tumor cells. However, the underlying specific mechanism has not been fully determined. Inhibiting the activation of NF-κB signaling pathway to promote the apoptosis is the topic of research on treating several conditions such as inflammation, immunity, and tumor. In this paper, the correlation between NF-κB signaling pathway and apoptosis of glioma cells is reviewed.

Keywords: Apoptosis and proliferation, glioma, nuclear factor-kappa B signaling pathway


How to cite this article:
Xu X, Yang H, Wang X, Tu Y. The significance of nuclear factor-kappa B signaling pathway in glioma: A review. Cancer Transl Med 2017;3:181-4

How to cite this URL:
Xu X, Yang H, Wang X, Tu Y. The significance of nuclear factor-kappa B signaling pathway in glioma: A review. Cancer Transl Med [serial online] 2017 [cited 2017 Nov 21];3:181-4. Available from: http://www.cancertm.com/text.asp?2017/3/5/181/210299


  Introduction Top


Glioblastoma multiforme is one of the most common malignant tumors, accounting for about 40% of intracranial tumors,[1] with high mortality and recurrence rate, among intracranial tumors.[2] At present, glioma is clinically treated by means of surgical resection, radiotherapy, and chemotherapy.[3],[4],[5] However, as glioma tumor often shows no clear boundaries with the adjacent normal brain tissue, associated with glioma cells' characteristics of invasive growth and uncontrolled proliferation, a complete surgical removal of the tumor tissue is hard to achieve. In addition, resistance of a glioma cell subpopulation to chemotherapy and radiotherapy results in an increased chance of relapse of the condition after surgery, making it a major cause of poor prognosis in glioma patients.[6] Hence, there is an urgent need to find more safe methods to effectively treat glioma condition. Inducing the apoptosis of glioma cells to inhibit their malignant transformation, proliferation, and metastasis could be one such promising method.

Nuclear factor-kappa B (NF-κB), first extracted from the B-lymphocytes by Sen and Baltimore[7] in 1986, is a very important transcription factor that exists in a wide variety of cells. It binds to the promoter of a variety of genes in a specific sequence to promote gene transcription and protein expression, and thus plays a variety of biological roles. NF-κB signaling pathway contains NF-κB family protein, NF-κB inhibitor protein, and NF-κB kinase complex.[8] In the cytoplasm, NF-κB is maintained in its nonactive form by complexing with IκB, but when subject to external stimuli, IκB proteins are phosphorylated and degraded, thereby activating NF-κB that reaches nucleus to activate antiapoptotic genes, thus promoting cell proliferation.[9]

NF-κB is the hub of intracellular signal transductions that are involved in the regulation of many physiological and pathological processes such as cell proliferation and apoptosis. Furthermore, NF-κB is increasingly expressed in a variety of malignant tumors such as pancreatic cancer, breast cancer, melanoma, and glioma.[10],[11],[12],[13] In recent years, a large number of studies have shown that NF-κB signaling pathway can mediate the occurrence and development of glioma by adjusting related transcription factors.[14],[15]


  Nuclear Factor-Kappa B Family Members and the Role of Related Proteins Top


A total of five NF-κB subunits were found in mammalian cells: RelA (p65), RelB, C-Rel, NF-κB1 (p50/p105), and NF-κB2 (p52/p100). The N-terminus of each NF-κB member contains approximately 300 amino acid residues that comprise Rel homology domain, the dimerization domain, DNA binding domain, and a nuclear localization signal domain, whose primary role is to mediate the binding specificity between Rel and DNA to promote the formation of dimers. p50 and p52 proteins were generated by the hydrolysis of p100 and p105 proteins; they contain specific anchor protein sequences, which can identify the specific binding sites of target genes, and thus play a role in regulating the expression of target genes. The carboxyl terminal of c-Rel, RelB, and p65 subunits contains a transcriptional activation domain, which, on external stimulation, can combine with the specific binding site on the target gene to promote its transcription. The NF-κB subunits may undergo homologous or heterologous dimerization, of which p50 and p65 are the most commonly detected heterodimers. The primary role of p65 heterodimer is to promote the initiation of gene transcription. In cell's resting state, the IκB-α serves as the inhibitor of p65 activity, thus inhibiting the gene transcription.[16] The primary six inhibitors of NF-κB protein family members are: IκB-α, IκB-β, IκB-γ (p105), IκB-δ (p100), IκB-ε, and Bcl-3. When subject to external stimulation, the major inhibitory protein IκB-α is rapidly decomposed so that the NF-κB is freed into the nucleus, with the assistance of p65 subunit, to participate in the regulation of cell proliferation, apoptosis, and gene transcription.[17]


  Mechanism of Nuclear Factor-Kappa B Signaling Pathway in the Regulation of Glioma Cell Apoptosis Top


NF-κB signaling pathway is a crucial part of many physiological and pathological processes, such as cell proliferation, cell apoptosis, and angiogenesis. A study found that the promoters or enhancers of the genes were associated with cell apoptosis and proliferation, such as C-myc, Cyclin D1, ICAM-1, Bcl-xL, and Bcl-2.[18] In other words, the activation of NF-κB may induce the expression of these genes, resulting in cell proliferation, antiapoptosis, and other biological effects.

Cells stimulated by external factors will quickly recruit a series of protein complexes, including receptor-interacting protein 1 (RIP1) and ubiquitin ligase (E3), such as TRAF2, TRAF5, cIAPl, and cIAP2. Further, the RIP1 is catalyzed by several or all E3 variants to form a K63 polyubiquitin chain, a key molecule in recruitment and activation of the downstream Iκβ kinase (IKK) complex. Among these IKK complexes, IKKy (NEMO) contains an ubiquitin-binding domain that binds to the ubiquitin chain that further phosphorylates and activates IKK and its downstream. This results in the release of NF-κB from Ikβ, which rapidly enters the nucleus and mediates the expression of Bcl-xL, Cyclin Dl, survivin, ICAM-1, and interleukin-8, and thus regulates the apoptosis and proliferation of glioma cells [Figure 1].
Figure 1: The mechanism of nuclear factor-kappa B release and its regulation of glioma cell apoptosis and proliferation

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NF-κB, as a nuclear transcription factor, regulates the expression of multiple genes in tumor cells and is closely related to the biological behavior of the tumor. In recent years, regulation of NF-κB signaling pathway in glioma cells has become a research hot spot in tumor field. Atkinson et al.[14] found that the NF-κB was increasingly expressed in glioma tissues, and the expression increased with the increase in glioma grade. Some studies have indicated that malignant glioblastoma tissues show constitutive activation of NF-κB.[19] In addition, Gill et al.[20] confirmed that NF-κB may affect the growth of glioblastoma cells. A continuous activation of NF-κB has been observed in surgical samples and cell lines of gliomas, and it has been reported that it can promote the growth and survival of glioma cells.[21] Further studies found that the activated NF-κB will lead to the proliferation and metastasis of diffuse gliomas.[22] In addition, NF-κB can regulate glioma cells' radiation sensitivity and aid in damage repair.[23]

There are several studies reporting that the regulation of NF-κB signaling pathway could affect the apoptotic mechanism of glioma cells. Studies have shown that the protease inhibitor PS-341 can block and downregulate the expression of NF-κB signaling pathway, thus restraining the proliferation and inducing the apoptosis of glioma cells.[24] Similarly, 2-methoxy-estradiol, an estrogen derivative, can also reduce the transcriptional activity and DNA binding activity of NF-κB by interfering with its signaling pathway, and thus induce cell apoptosis.[25] Hence, one can speculate that the activity of NF-κB signaling pathway on the apoptosis of glioma cells can be regulated by altering the expression of FLIP gene, which can interfere with the activity of caspase cascade.[26] Moreover, NF-κB pathways in human glioblastoma cells are activated after pretreatment with lipopolysaccharide or aluminum sulfate, which results in a large number of glioma cell proliferation.[27] In addition, glial cell maturation factor,[28] TNF-α[29] as well as chemotherapy and radiotherapy [30] and other factors leading to NF-κB pathway, are activated in glioma cells, which play a role in the regulation of cell proliferation.


  Therapeutic Strategies for Nuclear Factor-Kappa B Signaling Pathway Top


With the in-depth studies, it has been gradually realized that the NF-κB signaling pathway is not only associated with the chronic inflammation, cell growth, and other physiological and pathological processes of the human body, but can also participate in the occurrence and development of cancer by promoting the tumor cell proliferation while inhibiting their apoptosis. More and more studies have reported the anticancer activity of several anti-inflammatory drugs, known to inhibit NF-κB signaling pathway.[31],[32] At present, several IKK inhibitors are being assessed for their anticancer activity, as they not only have the ability to resist inflammation, but also can reduce the proliferation of tumor cells and enhance their sensitivity to radiotherapy and chemotherapy, and thus are expected to become a new line of anticancer drugs. Normally, inhibition of the expression of NF-κB target gene can increase the sensitivity of tumor cells to anticancer therapies. For example, inhibiting NF-κB decreases the expression of Bcl-2, IAP, and other family members, which in turn increases the sensitivity of the tumor cell to the radiotherapy and chemotherapy. Therefore, inhibiting the activation of NF-κB can accelerate the glioma cell death.[33] Recent studies have found that the proteasome inhibitors and other compounds can indirectly inhibit activation of NF-κB.[34],[35],[36] PS-341, a proteasome inhibitor that can selectively inhibit the proteasome 26S involved in a variety of regulatory proteasome degradation process, can damage I NF-κB and inactivate NF-κB. At present, few new promising IKK inhibitors are being assessed in clinical trials, which are hoped to effectively inhibit the activity of NF-κB signaling pathway and control cancer development.


  Conclusion And Future Prospects Top


NF-κB regulates polyphenic transcription and plays an important physiological role through the synergistic action with other transcription factors. This process is closely related to the occurrence and development of tumor. Studies have indicated that the activation of NF-κB signaling pathway plays a very important role in the occurrence and development of glioma. Although there are many signaling pathways which can reduce the activation of NF-κB pathway, there are few reports on the correlation between these signaling pathways and gliomas. Taking into account the physiological role of NF-κB, it is a challenge to hinder its antiapoptotic effect in glioma cells without affecting the body's normal gene transcription, and thus it is the focus of future research.

Financial support and sponsorship

This work was funded by the National Natural Scientific Foundation of China (No. 81572983).

Conflicts of interest

There are no conflicts of interest.

 
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