Reduced Levels of Misfolded and Aggregated Mutant p53 by Proteostatic Activation

Abstract

In malignant cancer, excessive amounts of mutant p53 often lead to its aggregation, a feature that was recently identified as druggable. Here, we describe that the induction of a heat-shock response by Foldlin, a small-molecule tool compound, reduced the protein levels of misfolded/aggregated mutant p53 while contact mutants or wild-type p53 remained largely unaffected. Foldlin also prevented the formation of stress-induced p53 nuclear inclusion bodies. In spite of our inability to identify a specific molecular target, Foldlin also reduced protein levels of aggregating SOD1 variants. Finally, by screening a library of 778 FDA-approved compounds for their ability to reduce misfolded mutant p53, we identified the proteasome inhibitor Bortezomib with similar cellular effects as Foldlin. Overall, the induction of a cellular heat shock response seems an effective strategy to deal with pathological protein aggregation. It remains to be seen however, how this strategy can be translated to a clinical setting.