NF-κB in colorectal cancer

Abstract

Colorectal cancer (CRC) is a leading cause of morbidity and mortality worldwide, responsible for more than half a million deaths annually. CRC is a multistep process that entails the accumulation of genetic/epigenetic aberrations, which lead to the simultaneous failure of protective mechanisms and the activation of tumorigenic pathways. In most cases of CRC a deregulation of the Wnt-signaling pathway is required. The transcription factor nuclear factor κB (NF-κB) has been recognized as a key player in the initiation and propagation of CRC. Under physiological conditions, NF-κB orchestrates the inflammatory process and participates in the modulation of various steps of cell cycle and survival. It is normally kept in an inactive state in the cytoplasm by binding to a group of inhibitory proteins. Upon receipt of a signal, its inhibitor is phosphorylated and proteolytically degraded and NF-κB is actively translocated to the nucleus, where it facilitates target-gene transcription. Recent experimental data reveal the important role of NF-κB in tumor cells as well as in the surrounding "cancerous" and reactive microenvironment. Various tumor cell-derived and contextual cues feed constantly this vicious circuitry sustaining inflammation and promoting proliferation, angiogenesis, invasion and eventually metastasis. Therefore NF-κB along with its upstream and downstream network presents a rational target for therapeutic interventions. Numerous small molecules, inhibitory peptides, antisense RNAs, natural compounds, as well as gene therapy strategies interfere with multiple steps of the NF-κΒ signaling cascade. The design of NF-κΒ-targeted treatment may aid the efforts towards the pursuit of more efficient therapeutic measures devoid of severe systemic side-effects.

The Potential Antitumor Effects of Capsaicin

“…A tumorigenic niche, composed of inflammatory cells, myofibroblasts, other cell types, and extracellular components, is essential for the maintenance of malignancies and facilitates tumor initiation, progression, and survival. Indeed, human colon cancer tissues are infiltrated by inflammatory cells and plasma levels of cytokines are often raised in CRC patients (Vaiopoulos et al 2013). Regulation of the inflammatory response is very complicated but many signaling pathways involve the transcription factor NFκB.…”

Downregulation of SAFB Sustains the NF-κB Pathway by Targeting TAK1 during the Progression of Colorectal Cancer

“…In CRC, cross-talk occurs between NF-kB and many other important signaling pathways, such as the RAS, AKT, and WNT signaling pathways. Together, these pathways form a complex network that regulates the progression of CRC (15,19). Our preliminary work and a published microarray analysis showed that the downregulation of SAFB expression increased the activation of NF-kB signaling in CRC, but the molecular mechanisms by which SAFB regulates the activation of NF-kB signaling are unclear.…”

A novel natural tautomeric pair of garcinielliptone FC suppressed nuclear factor κB and induced apoptosis in human colorectal cancer cells

“…Recently, a connection between inflammation and carcinogenesis has been evidenced. NF-κB is a transcription factor, which regulates essential pathways involved in the initiation and propagation of colorectal cancer by controlling inflammation, the cell cycle, and cell survival (Vaiopoulos, Athanasoula, & Papavassiliou, 2013). Overexpression and constitutive activation of NF-κB have been observed in colorectal cancer, especially in colitis-associated colorectal cancer (Grivennikov et al, 2009).…”

“…The results of human clinical trials have further revealed that regular use of nonsteroidal antiinflammatory drugs is associated with a decrease of incidence and mortality of colorectal cancer (Algra & Rothwell, 2012;Flossmann & Rothwell, 2007). NF-κB signalling also controls the growth, angiogenesis, and metastasis of colorectal cancer (Vaiopoulos et al, 2013). In addition, NF-κB suppressed apoptosis by modulating XIAP, c-Jun, and reactive oxygen species (Weng, Feng, Qin, & Ma, 2014).…”