that the p65/β-catenin complex changes dynamically over time in response to TNF-α stimulation and acute liver injury. Whereas basal p65/β-catenin association prevented NF-κB activation during resting conditions, upon TNF-α signaling, the p65/β-catenin complex underwent dissociation, allowing nuclear p65 translocation that regulated cell survival through expression of specific Idelalisib nmr antiapoptotic downstream targets. The relevance of p65/β-catenin association was demonstrated by manipulating β-catenin levels. We observed greater p65 activity upon silencing of the β-catenin gene. However, ICG-001, a known blocker of β-catenin’s downstream transcriptional activity through blockade of the β-catenin/CBP complex, decreases p65 reporter activity.38 This is not surprising, because ICG-001 treatment does not decrease total β-catenin levels; in fact, its free pool is increased.27 This result thus shows that not all anti-β-catenin therapies will be effective in stimulating NF-κB signaling, and only those agents that decrease total β-catenin levels and not its activity alone may be useful, because it is the physical presence of β-catenin protein that directly affects p65 activity through formation of the inhibitory complex. Nonetheless, β-catenin inhibition to enhance p65 activation Copanlisib nmr may be therapeutically exploitable
to treat certain hepatic injuries
where TNF-α signaling is the chief perpetrator. We also demonstrate that stabilizing β-catenin by LiCl treatment selleck compound represses p65 activity. Although inhibition of GSK-3β may inhibit p65 directly, this effect is likely due to increased β-catenin binding to p65 as reported.39 It is possible that the APC/Axin/GSK-3β/β-catenin complex may be in close proximity to or in direct association with the β-catenin/NF-κB/IκB complex. If true, this association could serve as a mode of cross-talk and integration of two distinct signaling pathways. Whether the p65/β-catenin complex exists as a part of a larger multimeric complex requires additional investigation. β-Catenin gene mutations leading to its activation and nuclear translocation are frequent in HCC, and as we have shown, this in turn leads to decreased p65 activity and expression in hepatoma cells and tissues. This is in agreement with previous reports that enhanced β-catenin can bind to and inhibit NF-κB transcriptional activation in cancer cells.22, 23 Although the functional consequences of this observation need to be investigated more thoroughly, it has been reported that β-catenin may act as a negative regulator of inflammation through repression of NF-κB signaling.40, 41 This may explain why in certain cases of β-catenin-mutated HCC, lesser cirrhosis is evident, because inflammation induces hepatic injury and fibrosis.