Signal-dependent regulation of gene expression as a target for cancer treatment: Inhibiting p38 alpha in colorectal tumors

In the last year, several evidences indicated that pharmacological manipulation of relevant signaling pathways couldselectively affect gene expression to influence cell fate. These findings render of extreme importance the elucidation ofhow external stimuli are transduced to mediate chromatin modifications, resulting in a permissive or repressive environ-ment for gene expression. These signaling cascades activate or repress the function of chromatin binding proteins that rep-resent attractive pharmacological targets for human diseases. Actually, the closer the target is to chromatin, the more thetranscriptional effect will be selective. Recent studies suggest that pharmacological manipulation of signaling pathways tomodulate cell fate is indeed possible and that chromatin-associated kinases could represent an optimal target. The p38MAPK is the prototype of this class of enzymes and its central role in the transcription process is evolutionary conserved.In this review we will focus on the possibility to inhibit p38ain colorectal cancer to arrest tumor progression and induceautophagic cell death. © 2008 Elsevier Ireland Ltd. All rights reserved.