Nuclear factor kappa-light-chain-enhancer of activated B cells, Mitogen-activated protein kinase kinase 1 and 2, Extracellular signal-regulated kinase, and Reactive oxygen species-sensitive pathways (NF-κB/MEK/ERK/ROS network)

The NF-κB, MEK1/2–ERK, and ROS-sensitive pathways constitute a highly integrated signaling network that governs cellular responses to environmental stress, cytokines, and growth factors (Oeckinghaus & Ghosh, 2009 [1]; McCubrey et al., 2007 [2]). Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factors essential for regulating genes involved in immunity, inflammation, and the prevention of apoptosis (Oeckinghaus & Ghosh, 2009 [1]). The MEK1/2–ERK cascade, part of the broader Mitogen-Activated Protein Kinase (MAPK) pathway, primarily drives cell proliferation, differentiation, and survival (McCubrey et al., 2007 [2]). Reactive Oxygen Species (ROS) act as secondary messengers that can activate these pathways through the oxidation of signaling proteins or by inactivating inhibitory phosphatases (Morgan & Liu, 2011 [3]). In many pathological conditions, particularly cancer and chronic inflammation, these pathways are constitutively active, leading to uncontrolled cell growth and resistance to therapy (McCubrey et al., 2007 [2]). Crosstalk between these systems allows cells to adapt to oxidative stress, often utilizing NF-κB and ERK to upregulate antioxidant defenses and pro-survival proteins (Morgan & Liu, 2011 [3]). Pharmacological intervention typically targets specific nodes within this network, such as MEK1/2 inhibitors for BRAF-mutant cancers or proteasome inhibitors to block NF-κB activation in multiple myeloma (Oeckinghaus & Ghosh, 2009 [1]; McCubrey et al., 2007 [2]). However, the complexity and redundancy of these pathways often lead to the development of drug resistance, necessitating combination therapies that hit multiple points in the network. Sources: [1] Oeckinghaus A, Ghosh S. Cold Spring Harb Perspect Biol. 2009;1(4):a000034. [2] McCubrey JA, et al. Leukemia. 2007;21(6):1072-1103. [3] Morgan MJ, Liu ZG. Cell Res. 2011;21(1):103-115.

Other names

NF-kappaB signalingMAPK/ERK pathwayROS-mediated stress responseSurvival and stress signaling networkNF-kB/MEK/ERK/ROS axis

Inhibition of MEK1/2 kinase activity, inhibition of the 26S proteasome to prevent IκB degradation and subsequent NF-κB nuclear translocation, and modulation of cellular redox status through antioxidant or pro-oxidant mechanisms.