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

David J. Barakat, Janet Mendonca, Theresa Barberi, Jing Zhang, Sushant Kachhap, Ido Paz-Priel, Alan David Friedman

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)152-161
Number of pages10
JournalCancer Letters
Volume375
Issue number1
DOIs
StatePublished - May 28 2016

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Lysosomes
Autophagy
Prostatic Neoplasms
Proteasome Endopeptidase Complex
Heterografts
Proteasome Inhibitors
Chloroquine
Autophagosomes
Bortezomib
Small Interfering RNA
Cell Death
Transcription Factors
Gene Expression
Growth
Genes

Keywords

  • Autophagy
  • C/EBPβ
  • Prostate cancer
  • Proteasome inhibitor
  • REDD1

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

C/EBPβ regulates sensitivity to bortezomib in prostate cancer cells by inducing REDD1 and autophagosome-lysosome fusion. / Barakat, David J.; Mendonca, Janet; Barberi, Theresa; Zhang, Jing; Kachhap, Sushant; Paz-Priel, Ido; Friedman, Alan David.

In: Cancer Letters, Vol. 375, No. 1, 28.05.2016, p. 152-161.

Research output: Contribution to journalArticle

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