Resistance to paclitxel in breast carcinoma cells requires a quality control of mitochondrial antiapoptotic proteins by TRAP1. Issue 5 (2nd May 2013) - Maddalena, Francesca
Abstract : TRAP1 is a mitochondrial antiapoptotic protein up‐regulated in several human malignancies. However, recent evidences suggest that TRAP1 is also localized in the endoplasmic reticulum (ER) where it is involved in ER stress protection and protein quality control of tumor cells. Based on the mechanistic link between ER stress, protection from apoptosis and drug resistance, we questioned whether these novel roles of TRAP1 are relevant for its antiapoptotic function. Here, we show for the first time that: i) TRAP1 expression is increased in about 50% of human breast carcinomas (BC), and ii) the ER stress protecting activity of TRAP1 is conserved in human tumors since TRAP1 is co‐upregulated with the ER stress marker, BiP/Grp78. Notably, ER‐associated TRAP1 modulates mitochondrial apoptosis by exerting a quality control on 18 kDa Sorcin, a TRAP1 mitochondrial client protein involved in TRAP1 cytoprotective pathway. Furthermore, this TRAP1 function is relevant in favoring resistance to paclitaxel, a microtubule stabilizing/ER stress inducer agent widely used in BC therapy. Indeed, the transfection of a TRAP1 deletion mutant, whose localization is restricted to the ER, in shTRAP1 cells enhances the expression of mitochondrial Sorcin and protects from apoptosis induced by ER stress agents and paclitaxel. Furthermore, BC cells adapted to paclitaxel or ER stress inducers share common resistance mechanisms: both cell models exhibit cross‐resistance to single agents and the inhibition of TRAP1 by siRNAs or gamitrinib, a mitochondria‐directed HSP90 family inhibitor, in paclitaxel‐resistant cells rescues the sensitivity to paclitaxel. These results support the hypothesis that ER‐associated TRAP1 is responsible for an extramitochondrial control of apoptosis and, therefore, an interference of ER stress adaptation through TRAP1 inhibition outside of mitochondria may be considered a further compartment‐specific molecular approach to rescue drug‐resistance. Highlights: TRAP1 and BiP/Grp78 are co‐upregulated in human breast carcinomas. TRAP1 protein quality control in the ER is relevant for its antiapoptotic function. TRAP1 quality control on mitochondrial Sorcin is involved in apoptosis prevention. TRAP1 mediates resistance to paclitaxel. Pharmacological inhibition of TRAP1 reverts resistance to paclitaxel.