C/EBPβ regulates sensitivity to bortezomib in prostate cancer cells by inducing REDD1 and autophagosome-lysosome fusion

The purpose of this study was to ascertain the mechanisms by which advanced prostate cancer cells resist bortezomib therapy. Several independent studies have shown that cells are protected from proteasome inhibition by increased autophagic activity. We investigated whether C/EBP beta, a transcription factor involved in the control of autophagic gene expression, regulates resistance to proteasome inhibition. In PC3 cells over-expressing C/EBP beta, turnover of autophagic substrates and expression of core autophagy genes were increased. Conversely, C/EBP beta knockdown suppressed autophagosome-lysosome fusion. We also found that C/EBP beta knockdown suppressed REDD1 expression to delay early autophagy, an effect rescued by exogenous REDD1. Cells with suppressed C/EBP beta levels showed delayed autophagy activation upon bortezomib treatment. Knockdown of C/EBP beta sensitized PC3 cells to bortezomib, and blockade of autophagy by chloroquine did not further increase cell death in cells expressing shRNA targeting C/EBP beta. Lastly, we observed a decreased growth of PC3 cells and xenografts with C/EBP beta knockdown and such xenografts were sensitized to bortezomib treatment. Our results demonstrate that C/EBP beta is a critical effector of autophagy via regulation of autolysosome formation and promotes resistance to proteasome inhibitor treatment by increasing autophagy. (C) 2016 Elsevier Ireland Ltd. All rights reserved.