( otein disposition. When stressed in thi...)Researchers shed light on mechanism of action used by anti-cancer drug

otein disposition. When stressed in this way, the cell responds to the protein load by reducing protein synthesis, increasing levels of protein chaperones, and by accelerating protein degradation. However, according to Grant, when ER stress exceeds a certain threshold, the ER stress response is converted from an adaptive to a pro-death response.

The team observed that exposure of cells to sorafenib resulted in the pronounced phosphorylation of a protein known as eIF2á, a process that serves as a critical brake on protein translation in cells subjected to ER stress. Interestingly, they also found that sorafenib, by virtue of its ability to inhibit Raf, also prevented an increase in expression of a chaperone protein known as Grp78, which is classically induced in the ER stress response, and which helps to resolve stresses associated with increased protein loads. The net effect of these actions was to induce a shutdown of protein synthesis accompanied by a dramatic increase in cell death.

“The notion that sorafenib acts by inhibiting protein synthesis and reducing expression of Mcl-1 suggests that this agent might be logically combined with other targeted agents whose antitumor activity is limited by Mcl-1 expression,” Grant said. Several such targeted agents are currently undergoing clinical evaluation in patients with various malignancies.

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Source:Virginia Commonwealth University

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