Abstract B18: Induction of tumor cell apoptosis by a proteasome deubiquitinase inhibitor is associated with oxidative stress and activation of JNK/AP1 mediated signaling.

Abstract

Abstract Tumor cells are dependent on a functioning ubiquitin-proteasome system (UPS), making it an ideal target for the development of anti-cancer therapies. The approval of bortezomib has verified this, however several problems have emerged including dose-limiting toxicity and tumor relapse. Thus there is an urgent need not only to identify new drugs but also new drug targets for the improved treatment of cancer patients. We recently identified the small molecule b-AP15 as an inhibitor of proteasome de-ubiquitinase (DUB) activity. b-AP15 inhibits the activity of two proteasome-associated DUBs, UCHL5 and USP14, resulting in defective poly-ubiquitin processing, proteasome shutdown, apoptosis and cell death in vitro and in vivo cancer models. Investigations into the mechanism of action showed that b-AP15 induced apoptosis via the induction of oxidative stress and activation of JNK/AP1 mediated stress signaling. Inhibition of the UPS with bortezomib or b-AP15 induced a similar stress response, characterized by ER stress, activation of the JNK/AP1 pathway and production of reactive oxygen species (ROS). Importantly pharmacological inhibition of JNK or treatment with ROS scavengers inhibited b-AP15-induced apoptosis without altering UPS inhibition. Our data suggests a role for ROS production and JNK signaling in proteasome DUB inhibitor induced apoptosis. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B18. Citation Format: Padraig D'Arcy, Slavica Brnjic, Magdalena Mazurkiewicz, Stig Linder. Induction of tumor cell apoptosis by a proteasome deubiquitinase inhibitor is associated with oxidative stress and activation of JNK/AP1 mediated signaling. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B18.