Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls

Abstract

Nuclear factor kappaB (NF-kappaB) transcription factors have a key role in many physiological processes such as innate and adaptive immune responses, cell proliferation, cell death, and inflammation. It has become clear that aberrant regulation of NF-kappaB and the signalling pathways that control its activity are involved in cancer development and progression, as well as in resistance to chemotherapy and radiotherapy. This article discusses recent evidence from cancer genetics and cancer genome studies that support the involvement of NF-kappaB in human cancer, particularly in multiple myeloma. The therapeutic potential and benefit of targeting NF-kappaB in cancer, and the possible complications and pitfalls of such an approach, are explored.

Figure 1. Human ca cancers that have been linked to constitutive NF-κB activation

Various hematological malignancies and solid tumors that exhibit constitutive NF-κB activation (adapted from ref. 17).

Figure 2. NF-κB target genes involved in cancer development and progression

NF-κB activation affects all six hallmarks of cancer through the transcription of genes involved in cell proliferation, angiogenesis, metastasis, inflammation and suppression of apoptosis as identified in both cell lines and tissue samples (adapted from r ref. 17).

Figure 3. NF-κB gain B gain- and loss loss-of of-function mutations in multiple myeloma

The classical and alternative NF-κB signaling pathways are represented downstream of CD40 and BAFF-R. Arrows indicate activating steps, and bars indicate inhibitory steps. Negative regulators subject to loss-of-function mutations are in red, and positive regulators affected by gain-of-function mutations are in green. Either type of mutations lead to NF-κB constitutive activation through NIK stabilization. The proteasome inhibitor bortezomib (BTZ) blocks both classical and alternative NF-κB signaling, whereas the IKKβ-specific inhibitor MLN120B (MLN) only blocks the classical NF-κB pathway. See text for further details.

Figure 4. cIAPs and IAP antagonists in the regulation of NF-κB and cell death pathways

Arrows indicate activating steps, and bars indicate inhibitory steps. IAP antagonists induce cIAP1 and cIAP2 proteosomal degradation, thus leading to activation of the classical and alternative NF-κB signaling through stabilization of NIK. IAP antagonists also induce TNF-α-dependent cell death. See text for further details.