title: C/EBPβ regulates sensitivity to bortezomib in prostate cancer cells by inducing REDD1 and autophagosome-lysosome fusion.
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.
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Barakat
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Mendonca
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Barberi
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Sushant K
authors.initials: SK
authors.lastname: Kachhap
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Ido
authors.initials: I
authors.lastname: Paz-Priel
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA. Electronic address: afriedm2@jhmi.edu.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Friedman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D000069286:Bortezomib / Q000494:pharmacology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008561:Membrane Fusion; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010588:Phagosomes / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; C469991:DDIT4 protein, human; D014157:Transcription Factors; D000069286:Bortezomib
keywords: Autophagy; C/EBPβ; Prostate cancer; Proteasome inhibitor; REDD1