1. C/EBPβ regulates sensitivity to bortezomib in prostate cancer cells by inducing REDD1 and autophagosome-lysosome fusion
- Author
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Ido Paz-Priel, Alan D. Friedman, Sushant Kachhap, Janet Mendonca, Jing Zhang, David J. Barakat, and Theresa Barberi
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Programmed cell death ,Cell Survival ,Gene Expression ,Antineoplastic Agents ,Mice, SCID ,Biology ,Membrane Fusion ,Article ,Small hairpin RNA ,Bortezomib ,03 medical and health sciences ,Mice, Inbred NOD ,Cell Line, Tumor ,Phagosomes ,Gene expression ,medicine ,Animals ,Humans ,Transcription factor ,Cell Proliferation ,Gene knockdown ,Binding Sites ,CCAAT-Enhancer-Binding Protein-beta ,Autophagy ,Prostatic Neoplasms ,Molecular biology ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,Cancer research ,Proteasome inhibitor ,Lysosomes ,medicine.drug ,Protein Binding ,Transcription Factors - Abstract
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/EBPβ, a transcription factor involved in the control of autophagic gene expression, regulates resistance to proteasome inhibition. In PC3 cells over-expressing C/EBPβ, turnover of autophagic substrates and expression of core autophagy genes were increased. Conversely, C/EBPβ knockdown suppressed autophagosome–lysosome fusion. We also found that C/EBPβ knockdown suppressed REDD1 expression to delay early autophagy, an effect rescued by exogenous REDD1. Cells with suppressed C/EBPβ levels showed delayed autophagy activation upon bortezomib treatment. Knockdown of C/EBPβ sensitized PC3 cells to bortezomib, and blockade of autophagy by chloroquine did not further increase cell death in cells expressing shRNA targeting C/EBPβ. Lastly, we observed a decreased growth of PC3 cells and xenografts with C/EBPβ knockdown and such xenografts were sensitized to bortezomib treatment. Our results demonstrate that C/EBPβ is a critical effector of autophagy via regulation of autolysosome formation and promotes resistance to proteasome inhibitor treatment by increasing autophagy.
- Published
- 2016