IKK/NF-kappaB signaling: balancing life and death--a new approach to cancer therapy

Abstract

IkappaB kinase/NF-kappaB (IKK/NF-kappaB) signaling pathways play critical roles in a variety of physiological and pathological processes. One function of NF-kappaB is promotion of cell survival through induction of target genes, whose products inhibit components of the apoptotic machinery in normal and cancerous cells. NF-kappaB can also prevent programmed necrosis by inducing genes encoding antioxidant proteins. Regardless of mechanism, many cancer cells, of either epithelial or hematopoietic origin, use NF-kappaB to achieve resistance to anticancer drugs, radiation, and death cytokines. Hence, inhibition of IKK-driven NF-kappaB activation offers a strategy for treatment of different malignancies and can convert inflammation-induced tumor growth to inflammation-induced tumor regression.

Figure 1

IKK/NF-κB signaling pathways. The classical pathway is activated by a variety of inflammatory signals, resulting in coordinate expression of multiple inflammatory and innate immune genes. The alternative pathway is strictly dependent on IKKα homodimers and is activated by lymphotoxin β receptor (LTβR), B cell–activating factor belonging to the TNF family (BAFF), and CD40 ligand (CD40L). The alternative pathway plays a central role in the expression of genes involved in development and maintenance of secondary lymphoid organs. BLC, B lymphocyte chemoattractant; ELC, Epstein-Barr virus–induced molecule 1 ligand CC chemokine; MCP-1, monocyte chemoattractant protein-1; MIP-1α, macrophage inflammatory protein-1α; PLA2, phospholipase A2; SDF-1, stromal cell–derived factor-1α; SLC, secondary lymphoid tissue chemokine.

Figure 2

Control of cell survival and death through NF-κB–JNK cross-talk. Positive feedback loops exist between ROS and caspases, caspases and JNK, and JNK and ROS. Negative feedback loops exist between NF-κB and caspases, and NF-κB and ROS. NF-κB functions as a pro-survival transcription factor by inducing the expression of antiapoptotic genes, such as the Bcl-2 family members and caspase inhibitors, and antioxidant genes, such as MnSOD and FHC. Activation of NF-κB also results in inhibition of prolonged JNK activation, mostly through inhibition of ROS accumulation. Inhibition of NF-κB enhances PCD, which can be either apoptotic or necrotic, by removing the negative feedback loops.

Figure 3

Inhibition of NF-κB in cancer cells converts inflammation-induced tumor growth to tumor regression. Activation of the innate and adaptive immune system can have profound influence on tumor growth and development. In addition to its role in activation of immune cells, NF-κB within the malignant cell is a major modulator of the tumor response to inflammation. Activation of NF-κB promotes tumor growth and confers resistance to death cytokines, such as TRAIL. Conversely, inhibition of NF-κB prevents inflammation-stimulated tumor growth and enhances inflammation-induced tumor regression mediated by TRAIL.