While NF-κB is considered to play key roles in the development and progression of many cancers, the mechanisms whereby this transcription factor is activated in cancer are poorly understood. A key oncoprotein in a variety of cancers is the serine–threonine kinase Akt, which can be activated by mutations in PI3K, by loss of expression/activity of PTEN, or through signaling induced by growth factors and their receptors. A key effector of Akt-induced signaling is the regulatory protein mTOR (mammalian target of rapamycin). We show here that mTOR downstream from Akt controls NF-κB activity in PTEN-null/inactive prostate cancer cells via interaction with and stimulation of IKK. The mTOR-associated protein Raptor is required for the ability of Akt to induce NF-κB activity. Correspondingly, the mTOR inhibitor rapamycin is shown to suppress IKK activity in PTEN-deficient prostate cancer cells through a mechanism that may involve dissociation of Raptor from mTOR. The results provide insight into the effects of Akt/mTOR-dependent signaling on gene expression and into the therapeutic action of rapamycin.

Abundant data support a key role for the transcription factor nuclear factor-κB (NF-κB) signaling pathway in controlling the initiation and progression of human cancer. NF-κB and associated regulatory proteins such as IκB kinase (IKK) are activated downstream of many oncoproteins and there is much evidence for the activation of NF-κB-dependent target genes in a variety of solid tumors and hematologic malignancies. This review focuses on the mechanisms by which the NF-κB pathway is activated in cancer and on the oncogenic functions controlled by activated NF-κB. Additionally, the effects of NF-κB activation in tumors relative to cancer therapy are also discussed.

The transcription factor NF-κB and associated regulatory factors (including IκB kinase subunits and the IκB family member Bcl-3) are strongly implicated in a variety of hematologic and solid tumor malignancies. A role for NF-κB in cancer cells appears to involve regulation of cell proliferation, control of apoptosis, promotion of angiogenesis, and stimulation of invasion/metastasis. Consistent with a role for NF-κB in oncogenesis are observations that inhibition of NF-κB alone or in combination with cancer therapies leads to tumor cell death or growth inhibition. However, other experimental data indicate that NF-κB can play a tumor suppressor role in certain settings and that it can be important in promoting an apoptotic signal downstream of certain cancer therapy regimens. In order to appropriately move NF-κB inhibitors in the clinic, thorough approaches must be initiated to determine the molecular mechanisms that dictate the complexity of oncologic and therapeutic outcomes that are controlled by NF-κB.

The NF-κB transcription factor pathway is a crucial regulator of inflammation and immune responses. Additionally, aberrant NF-κB signaling has been identified in many types of cancer. Downstream of key oncogenic pathways, such as RAS, BCR-ABL, and Her2, NF-κB regulates transcription of target genes that promote cell survival and proliferation, inhibit apoptosis, and mediate invasion and metastasis. The cancer stem cell model posits that a subset of tumor cells (cancer stem cells) drive tumor initiation, exhibit resistance to treatment, and promote recurrence and metastasis. This review examines the evidence for a role for NF-κB signaling in cancer stem cell biology.

The glutamate transporter gene, EAAT2/GLT‐1, is induced by epidermal growth factor (EGF) and downregulated by tumor necrosis factor α (TNFα). While TNFα is generally recognized as a positive regulator of NF‐κB‐dependent gene expression, its ability to control transcriptional repression is not well characterized. Additionally, the regulation of NF‐κB by EGF is poorly understood. Herein, we demonstrate that both TNFα‐mediated repression and EGF‐mediated activation of EAAT2 expression require NF‐κB. We show that EGF activates NF‐κB independently of signaling to IκB. Furthermore, TNFα can abrogate IKKβ‐ and p65‐mediated activation of EAAT2. Our results suggest that NF‐κB can intrinsically activate EAAT2 and that TNFα mediates repression through a distinct pathway also requiring NF‐κB. Consistently, we find that N‐myc is recruited to the EAAT2 promoter with TNFα and that N‐myc‐binding sites are required for TNFα‐mediated repression. Moreover, N‐myc overexpression inhibits both basal and p65‐induced activation of EAAT2. Our data highlight the remarkable specificity of NF‐κB activity to regulate gene expression in response to diverse cellular signals and have implications for glutamate homeostasis and neurodegenerative disease.