NF-κB: A Stress-Regulated Switch for Cell Survival

Abstract

Nuclear factor-kappaB (NF-kappaB), a stress-regulated transcription factor belonging to the Rel family, has a pivotal role in the control of the inflammatory and the innate immune responses. Its activation rapidly induces the transcription of a variety of genes encoding cell adhesion molecules, inflammatory and chemotactic cytokines, cytokine receptors, and enzymes that produce inflammatory mediators. More recently, NF-kappaB activation has been connected with multiple aspects of oncogenesis, including the control of cell proliferation, migration, cell cycle progression, and apoptosis. Interestingly, NF-kappaB is constitutively activated in several types of cancer cells, including hematological and epithelial malignancies. In addition, activation of NF-kappaB in cancer cells by chemotherapy or radiation therapy has been associated with the acquisition of resistance to apoptosis, which has emerged as a significant impediment to effective cancer treatment. Selective cyclopentenone inhibitors of the IkappaB kinase, the key enzyme controlling NF-kappaB activation, were recently shown to be potent inducers of apoptosis in chemoresistant lymphoid malignancies. Increasing evidence, summarized in this review, indicates that the development of selective NF-kappaB inhibitors may represent a promising therapeutic tool to sensitize tumor cells to apoptosis and increase the efficacy of conventional anticancer drugs in a wide spectrum of malignancies.

Radiation-triggered Tumor Necrosis Factor (TNF) α-NFκB Cross-signaling Favors Survival Advantage in Human Neuroblastoma Cells

“…Disruption of aberrantly regulated survival signaling mediated by NFB has recently become an important task in the therapy of several chemoresistant and radioresistant cancers (15). IAPs are expressed at high levels in many tumors and have been reported to contribute to the resistance of cancers to therapy including resistance to radiotherapy (45).…”

“…We identified that IR profoundly activates NFB in human NB cells (13,14), leading to induced radioprotection, and further that forced inhibition of NFB enhanced IR-induced cell death. To that end, disruption of aberrantly regulated survival signaling mediated by NFB has recently become an important task in the therapy of several chemoresistant/ radioresistant cancers (15). However, mechanistic orchestration of NFB after clinical doses of IR and its functional role in induced survival advantage and/or tumor recurrence is poorly understood.…”

Two MicroRNAs Encoded within the Bovine Herpesvirus 1 Latency-Related Gene Promote Cell Survival by Interacting with RIG-I and Stimulating NF-κB-Dependent Transcription and Beta Interferon Signaling Pathways

“…Interestingly, dexamethasone, which stimulates BHV-1 reactivation from latency, impairs NF-B signaling (22,86). Heat stress stimulates HSV-1 in vivo reactivation from latency in mice (68) and, like dexamethasone, impairs NF-B signaling (5,63). Thus, there appears to be a link between disrupting NF-B signaling, inducing apoptosis, and increasing the incidence of reactivation from latency.…”

Genetic polymorphisms in the oxidative stress pathway and susceptibility to non-Hodgkin lymphoma

“…In response to stress conditions such as infection and inXammation, an inactive form of NF-B present in the cytoplasm can be activated. Activated NF-B transcription factors have been associated with several features of tumorigenesis, including the proliferation, diVerentiation, and survival of lymphocytes (Piva et al 2006). In addition, there is evidence that NF-B activity plays an important role in the pathogenesis of activated B-cell-like DLBCL cell lines (Davis et al 2001;Alizadeh et al 2000), which is critical in lymphomagenesis.…”