The diverse and complex roles of NF-κB subunits in cancer

Key Points The nuclear factor-κB (NF-κB)–inhibitor of NF-κB kinase (IKK) pathway can promote the growth and survival of many solid and haematological maligancies and therefore has the potential to provide numerous targets for novel anticancer therapies. Most attention has focused on the development of IKKβ inhibitors, but it is now clear that IKKβ has many NF-κB-independent functions and its inhibition could result in undesired effects. Although it is apparent that NF-κB subunits have important roles in tumorigenesis and the response to cancer therapy, their individual contributions have not been clearly defined. The NF-κB response is highly pleiotropic and the consequences of its activation can be context dependent. NF-κB is not always tumour promoting and it can exhibit tumour suppressor-like activities. Crosstalk with tumour-suppressor proteins, such as p53, provides an important mechanism for regulating NF-κB activity and function in cancer. Tumour suppressors can inhibit the tumour-promoting activities of NF-κB subunits while facilitating their ability to suppress cancer progression. Understanding the regulation and function of the NF-κB subunits in cancer provides opportunities for the development of new therapies and allows the better use of existing drugs that affect NF-κB–IKK activity. Nuclear factor-κB (NF-κB) has many functions in cancer, hence the need for drugs that can modulate its activity. In order to achieve this, Neil D. Perkins argues that the complex roles of the individual NF-κB subunits must be considered. It is only recently that the full importance of nuclear factor-κB (NF-κB) signalling to cancer development has been understood. Although much attention has focused on the upstream pathways leading to NF-κB activation, it is now becoming clear that the inhibitor of NF-κB kinases (IKKs), which regulate NF-κB activation, have many independent functions in tissue homeostasis and normal immune function that could compromise the clinical utility of IKK inhibitors. Therefore, if the NF-κB pathway is to be properly exploited as a target for both anticancer and anti-inflammatory drugs, it is appropriate to reconsider the complex roles of the individual NF-κB subunits.