Abstract 1708: Metabolic regulation of the ubiquitin+proteasome system.

Abstract The ubiquitin+proteasome system (UPS) is a highly complex network that maintains protein homeostasis and cell viability through the highly regulated and selective turnover of targeted proteins. The proteasome is the major intracellular protease in eukaryotes and serves as the catalytic core of the UPS. The cytotoxic effect of proteasome inhibition has been translated therapeutically to dramatically improve the overall survival of patients diagnosed with the plasma cell malignancy multiple myeloma (MM). Bortezomib has emerged as the standard-of-care therapy for MM to catapult the UPS into a position of prominence in cancer biology and drug development but significant obstacles remain since many patients do not respond to bortezomib, clinical responses are not sustained and drug resistance inevitably emerges through unknown mechanisms. Gene profiling was performed as an unbiased approach to address the precise molecular events that promote bortezomib-resistance. Results indicated that effectors of energy metabolism were differentially expressed in cells resistant to bortezomib. Subunits of the cellular energy sensor AMP-activated protein kinase (AMPK) were expressed at lower levels in resistant cells relative to the parental cells. Real-time, cell-based metabolic measurements demonstrated that bortezomib rapidly and dramatically reduced tumor cell oxygen-consumption while bortezomib-resistant cells were less sensitive to metabolic deregulation. Genetic ablation of the AMPKα1/α2 encoding-genes also reduced the effect of bortezomib to promote autophagosome formation as well as bortezomib-induced cytotoxicity. Similarly, knockout of the AMPK-substrate and autophagy-initiating kinase ULK1 also reduced bortezomib-induced autophagosome formation and cell death. Proteasome inhibition promoted ULK-1 association with the autophagosome initiators ATG13, FIP200 and beclin-1. The AMPK activator AICAR further enhanced bortezomib-induced cytotoxicity in myeloma, lymphoma, leukemic and solid tumor cells. Proteasome inhibitors induce AMPK+ULK-mediated autophagosome formation that is coupled to apoptosis and can be exploited as a novel anti-cancer therapeutic strategy. Citation Format: James J. Driscoll, Sajjeev Jagannathan. Metabolic regulation of the ubiquitin+proteasome system. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1708. doi:10.1158/1538-7445.AM2013-1708