Targeting NF-κB Signaling in Cancer Stem Cells: A Narrative Review

Abstract

Among the cell populations existing within a tumor, cancer stem cells are responsible for metastasis formation and chemotherapeutic resistance. In the present review, we focus on the transcription factor NF-κB, which is present in every cell type including cancer stem cells. NF-κB is involved in pro-tumor inflammation by its target gene interleukin 1 (IL1) and can be activated by a feed-forward loop in an IL1-dependent manner. Here, we summarize current strategies targeting NF-κB by chemicals and biologicals within an integrated cancer therapy. Specifically, we start with a tyrosine kinase inhibitor targeting epidermal growth factor (EGF)-receptor-mediated phosphorylation. Furthermore, we summarize current strategies of multiple myeloma treatment involving lenalidomide, bortezomib, and dexamethasone as potential NF-κB inhibitors. Finally, we discuss programmed death-ligand 1 (PD-L1) as an NF-κB target gene and its role in checkpoint therapy. We conclude, that NF-κB inhibition by specific inhibitors of IκB kinase was of no clinical use but inhibition of upstream and downstream targets with drugs or biologicals might be a fruitful way to treat cancer stem cells.

Keywords: EGF; NF-κB; PD-L1; bortezomib; cancer stem cells; dexamethasone; lenalidomide.

Figure 1

CSC- as well as incorporated cancer cell characteristics. Features and benefits for survival/maintenance of CSCs and (partially) differentiated cancer cells, whereas magenta characteristics exclusively describe cells possessing the stemness character.

Figure 2

NF-κB signaling involves at least two different pathways: An alternative pathway with upstream kinase NIK and a dimer of IKK-1. In this pathway, the precursor of p52 acts as an inhibitory subunit. The classical pathway involves a dimer of upstream kinases (TAK1, TAB), which could activate a trimeric signalosome composed of NEMO (docking component), IKK-1, and IKK-2. Activation of signalosome leads to phosphorylation of IκB-α at serine 32 and 36, followed by ubiquitination and subsequent degradation within the proteasome. For further details, see the text.

Figure 3

Overview of biologicals (anti-IL1β, anti-PDL-1) and small molecules such as RTK-inhibitors (RKI) for targeting NF-κB-signaling in cancer and CSCs.

Figure 4

Anti-inflammatory cues impinging on NF-κB in CSCs. On the left, a CSC with NF-κB-signaling is depicted. NF-κB could be activated by cancer-produced IL-1. Inhibition of NF-κB-activation could be mediated by several members of the IκB family, by the de-ubiquitination of signaling molecules (for details see text). Furthermore, non-coding RNAs such as microRNA(miR) 146 or long non-coding RNAs NKILA could inhibit NF-κB-activation by targeting activating proteins. Inhibition of transactivation could be driven by IEX-1 or by COMMD1-mediated ubiquitination of RELA. On the right side, tumor-infiltrating immune cells are shown. Naïve CD4⁺ cells can differentiate into induced regulatory T cells (iTregs). These express ectoenzymes such as CD39 and CD73 responsible for the hydrolysis of ATP to adenosine, in turn, inhibiting NF-κB-activation in CSCs. iTREGs could fancy cREL for expression of FOXP3 lineage transcription factor. A pro-tumor function of iTREGs could be the repression of CD8 cytotoxic lymphocytes (CTL).