The multifaceted NF-kB: are there still prospects of its inhibition for clinical intervention in pediatric central nervous system tumors?

Abstract

Despite advances in the understanding of the molecular mechanisms underlying the basic biology and pathogenesis of pediatric central nervous system (CNS) malignancies, patients still have an extremely unfavorable prognosis. Over the years, a plethora of natural and synthetic compounds has emerged for the pharmacologic intervention of the NF-kB pathway, one of the most frequently dysregulated signaling cascades in human cancer with key roles in cell growth, survival, and therapy resistance. Here, we provide a review about the state-of-the-art concerning the dysregulation of this hub transcription factor in the most prevalent pediatric CNS tumors: glioma, medulloblastoma, and ependymoma. Moreover, we compile the available literature on the anti-proliferative effects of varied NF-kB inhibitors acting alone or in combination with other therapies in vitro, in vivo, and clinical trials. As the wealth of basic research data continues to accumulate, recognizing NF-kB as a therapeutic target may provide important insights to treat these diseases, hopefully contributing to increase cure rates and lower side effects related to therapy.

Keywords: Inhibitors; NF-kB; Pediatric tumors; Treatment.

Fig. 1

NF-κB pathway. The canonical pathway (left) is responsible for the activation of the p50/p65 dimer via IκB degradation. The non-canonical pathway (right), in turn, is dependent on NIK and triggers the activation of the p52/RelB dimer via processing and removal of the C-terminal portion of the p52 precursor, p100. In both pathways, once the dimers are activated, they are translocated to the nucleus, and with the help of adapter proteins, promote gene transcription. Ub ubiquitin, P phosphoryl group

Fig. 2

Dysregulation of NF-κB pathway in cancer. Altered NF-κB pathway activation in cancer can occur basically in two different ways, directly or indirectly. In the first case, changes in proteins of the NF-κB pathway occur, such as mutations in IKK that make it constitutively active and capable of phosphorylating IkB without the need for signaling; mutations that make IκB inactive and thus the NF-κB dimers remain free to be translocated to the nucleus; mutations can also occur in the subunits of the NF-κB dimers that make them more stable and/or with greater affinity for DNA and/or lead to an increase in their expression. The indirect activation may result from increased concentration of growth factors in the extracellular medium, changes in the extracellular matrix components, or changes in other oncogenic pathways. Two well-known examples in brain tumors are the EGFR mutation, EGFRvIII, which has constitutive activation, and Ras mutations that activate NF-κB via Akt, and/or mTORC2 and via MAPK, respectively

Fig. 3

NF-κB regulates the expression of a variety of genes involved in tumor growth and progression. Herein, the known targets of this transcription factor were grouped according to each cancer hallmark in which they participate: sustained proliferation and tumor growth, activation of invasion and metastasis, instability and genomic mutation, chemotherapy and radioresistance, resistance to cell death and survival, immunological regulators and inflammation, energy and cellular metabolic dysregulation and induction of angiogenesis. (Image constructed from http://www.nf-kb.org and www.servier.com)

Fig. 4

Pediatric central nervous system tumor gene expression profiles. Data were retrieved from the R2 online platform: Genomics Analysis and Visualization Platform (http://r2.amc.n; library: Mixed Tumor Ependymoma—Foreman—149—MAS5.0—u133p2; probes: RELA 209878_s_at, RELB 205205_at, REL 206036_s_at, NFKB1 209239_at, NFKB2 207535_s_at.) and heatmaps created on the Heatmapper website (http://www2.heatmapper.ca/expression/). The same data were used to perform a Spearman’s correlation in GraphPad Prism 8, considering p > 0.05 as significant. Similar expression and correlation profiles between ependymoma, medulloblastoma, pediatric high-grade glioma, and pilocytic astrocytoma are observed, with high expression of genes from the REL family when compared to normal tissues

Fig. 5

NF-κB interacts with the main proteins/pathways active in each MB subgroup. In the WNT group, cross-talk occurs between the Wnt/β-catenin and NF-κB pathways. Overexpression of β-catenin or Wnt proteins increase the expression of βTrCP, which is responsible for increasing the degradation of IκB-α and, consequently, the transactivation of NF-κB. In the SHH group and in Group 3, activation of the NF-κB pathway is responsible for transcribing SHH and MYC, respectively, known to be molecular markers for each group. In turn, Group 4 is characterized by a deletion of NFKBIA, a gene that transcribes the IκB protein, leading to the constitutive activation of NF-κB [75, 141, 440]

Fig. 6

NF-κB inhibitors can act on different stages of its activation. The underlying mechanisms include the blockage of IKK and IκB phosphorylation, IκB proteasome degradation, p65 phosphorylation, nuclear translocation, and DNA binding. Inhibition of this pathway in tumors can promote apoptosis, reduce proliferation, angiogenesis and metastasis. Moreover, NF-κB hindrance can improve the cytotoxicity of commonly used therapies

Fig. 7

Venn’s Diagram of inhibitors acting on each NF-kB subunit. Drugs were assessed through canSAR BLACK 1.4.0 (https://cansarblack.icr.ac.uk/) and available literature [–430]. Note that ~ 75% of compounds are described as inhibitors of 3 out of 5 subunits, RELA, NFKB1, and NFKB2. Individual compound and their specificity are depicted in supplementary table 1

Fig. 8

Vulnerability of CNS cell lines to NF-κB depletion. Dependency data were retrieved from the DepMap consortium (CRISPR (Avana) Public 20Q4 [416] (https://depmap.org/portal/). Cell lines selected included glioblastoma (adult and pediatric) and pediatric medulloblastoma. Dependency scores for each cell line are depicted in Supplementary Table 2. Lower scores correspond to greater gene dependency