UCP2 inhibition induces ROS/Akt/mTOR axis: role of GAPDH nuclear translocation in genipin/everolimus anticancer synergism.

UCP2 inhibition induces ROS/Akt/mTOR axis: role of GAPDH nuclear translocation in genipin/everolimus anticancer synergism. Free Radic Biol Med. 2017 Sep 26;: Authors: Dando I, Pacchiana R, Pozza ED, Cataldo I, Bruno S, Conti P, Cordani M, Grimaldi A, Butera G, Caraglia M, Scarpa A, Palmieri M, Donadelli M Abstract Several studies indicate that mitochondrial uncoupling protein 2 (UCP2) plays a pivotal role in cancer development by decreasing reactive oxygen species (ROS) produced by mitochondrial metabolism and by sustaining chemoresistance to a plethora of anticancer drugs. Here, we demonstrate that inhibition of UCP2 triggers Akt/mTOR pathway in a ROS-dependent mechanism in pancreatic adenocarcinoma cells. This event reduces the antiproliferative outcome of UCP2 inhibition by genipin, creating the conditions for the synergistic counteraction of cancer cell growth with the mTOR inhibitor everolimus. Inhibition of pancreatic adenocarcinoma cell growth and induction of apoptosis by genipin and everolimus treatment are functionally related to nuclear translocation of the cytosolic glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The synthetic compound (S)-benzyl-2-amino-2-(S)-3-bromo-4,5-dihydroisoxazol-5-yl-acetate (AXP3009), which binds GAPDH at its redox-sensitive Cys152, restores cell viability affected by the combined treatment with genipin and everolimus, suggesting a role for ROS production in the nuclear trans...
Source: Free Radical Biology and Medicine - Category: Biology Authors: Tags: Free Radic Biol Med Source Type: research