New insights into TRAP1 pathway.

Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1) is a mitochondrial heat shock protein involved in the protection from DNA damages and apoptosis induced by oxidants and several other stress conditions. Despite the well-characterized role in the regulation of mitochondrial integrity, through the interaction with cyclophilin D, a mitochondrial permeability transition pore regulator, several recent studies contributed to draw a more complex "picture" of the TRAP1 pathway: most of these updated functions arise from the identification of novel specific TRAP1 "client" proteins and from the recent discovery of multiple subcellular localizations/functions for this chaperone. This review briefly highlights some general features of TRAP1, and among others its role in cytoprotection, summarizing many different functions, which contribute to its protective role upon several stress inducers. Of note, particular emphasis is given to the recent findings on the regulation of Endoplasmic Reticulum stress and protein quality control by TRAP1, as well as to its role in regulating calcium homeostasis throughout its client protein Sorcin. Starting from the above observations a preliminary "TRAP1 signature" is provided and a new intriguing and interesting field to explore is discussed. Several questions are still open given the complexity of such mechanisms. However, by translating these recent insights at the molecular and cellular levels into personalized individual anticancer treatments, designing novel strategies based on the simultaneous inhibition of multiple tumor-specific pathways, and contemplating subcellular-targeted approaches aimed at reverting drug resistance and improving antitumor activity the struggle to combat cancer become more successful and closer.