TY - JOUR T1 - Oncogenic addiction to high 26S proteasome levels JF - bioRxiv DO - 10.1101/211300 SP - 211300 AU - Peter Tsvetkov AU - Julia Adler AU - Nadav Myers AU - Assaf Biran AU - Nina Reuven AU - Yosef Shaul Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/10/30/211300.abstract N2 - Proteasomes are large intracellular complexes responsible for the degradation of cellular proteins. The altered protein homeostasis of cancer cells results in increased dependency on proteasome function. There are several different proteasome complexes that may be assembled in cells, with the 20S catalytic core common to them all. 20S proteasomes can function in isolation, or as part of larger complexes (26S) with regulatory particles (RP) such as the 19S that is needed for the targeting and processing of ubiquitinated substrates. Proteasome inhibitors target the catalytic barrel (20S) and thus this inhibition does not allow the deconvolution of the distinct roles of 20S vs. 26S proteasomes in cancer progression. We examined the degree of dependency of cancer cells specifically to the level of the 26S proteasome complex. We found that oncogenic transformation of human and mouse immortalized cells with mutant Ras induced a strong increase in the translation of the 26S proteasome subunits, giving rise to high 26S complex levels. We show that depletion of a single subunit of the 19S RP was sufficient to significantly reduce the 26S proteasome level and lower the cellular 26S/20S ratio. We further demonstrate that the accumulated 26S proteasome was essential for the viability of the transformed cells. Moreover, the viability of 20 different cancer cell lines, but not normal human fibroblasts, was severely compromised upon specific 26S proteasome suppression regardless of their p53 status. Suppression of 26S activated the UPR and Caspase-3, which at least partially explains the cell-killing effect. Morphologically, suppression of the 26S proteasome resulted in cytoplasm shrinkage and nuclear deformation. Thus, the tumor cell-specific addiction to high 26S proteasome levels sets the stage for future strategies in cancer therapy. ER -