The Two Faces of NF-κB Signaling in Cancer Development and Therapy

Abstract

Constitutive activation of NF-κB signaling can promote oncogenesis, providing a rationale for anticancer strategies that inhibit NF-κB signaling. Two recent publications in Genes & Development provide evidence that, in contexts where prosurvival signals derive from other oncogenes, NF-κB activity instead enhances sensitivity to cytotoxic chemotherapy, thereby exerting a tumor-suppressor function.

Figure 1. Model for the Context-Dependent Opposing Roles of NF-κB Signaling in Cancer Development and Therapy

(A) In tumors with genetic mutations in NF-κB pathway components leading to constitutive NF-κB signaling, the pro-survival BCL2 oncogene is upregulated. In these tumors, such as ABC-DLBCL, NF-κB inhibitors are beneficial as they counteract the oncogenic function of NF-κB and would promote tumor cell death. (B) In tumors where the pro-survival signal derives from NF-κB-independent BCL2 overexpression, a functional NF-κB pathway is required to mediate the therapy-induced senescence response by activating the transcription of genes of SASP. In this scenario, such as in GCB DLBCL, NF-κB inhibitors are detrimental as they interfere with the senescence response that would normally promote tumor cell death.