ROS inhibitor N-acetyl-L-cysteine antagonizes the activity of proteasome inhibitors

In this study, we identified inhibition of proteasome inhibitors as a novel activity of NAC. Both NAC and catalase, another known scavenger of ROS, similarly inhibited ROS levels and apoptosis associated with H2O2. However, only NAC, but not catalase or another ROS scavenger Trolox was able to prevent effects linked to proteasome inhibition, such as protein stabilization, apoptosis and accumulation of ubiquitin conjugates. These observations suggest that NAC has a dual activity as an inhibitor of ROS and proteasome inhibitors. Recently, NAC was used as a ROS inhibitor to functionally characterize a novel anticancer compound, piperlongumine leading to its description as a ROS inducer. In contrast, our experiments showed that this compound depicts features of proteasome inhibitors including suppression of FOXM1, stabilization of cellular proteins, induction of ROS-independent apoptosis and enhanced accumulation of ubiquitin conjugates. In addition, NAC, but not catalase or Trolox interfered with the activity of piperlongumine, further supporting that piperlongumine is a proteasome inhibitor. Most importantly, we showed that NAC, but not other ROS scavengers, directly binds to proteasome inhibitors. To our knowledge, NAC is the first known compound that directly interacts with and antagonizes the activity of proteasome inhibitors. Altogether, our data suggest that as a result of the dual nature of NAC data interpretation might not be straightforward when NAC is utilized as an an...

Source: BJ Signal - June 18, 2013 Category: Biochemistry Authors: M Halasi, M Wang, T S Chavan, V Gaponenko, N Hay, A L Gartel Tags: BJ ChemBio Source Type: research