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

被引：35

作者：

Barakat, David J. ^{[1
]}

Mendonca, Janet ^{[1
]}

Barberi, Theresa ^{[1
]}

Zhang, Jing ^{[1
]}

Kachhap, Sushant K. ^{[1
]}

Paz-Priel, Ido ^{[1
]}

Friedman, Alan D. ^{[1
]}

机构：

[1] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA

来源：

CANCER LETTERS | 2016年 / 375卷 / 01期

关键词：

Autophagy; C/EBP beta; REDD1; Prostate cancer; Proteasome inhibitor; PROTEASOME INHIBITORS ACTIVATE; ENDOPLASMIC-RETICULUM STRESS; MAMMALIAN TARGET; PROTEIN; DEATH; RESISTANCE; DOCETAXEL; MECHANISM; GENE; LC3;

D O I：

10.1016/j.canlet.2016.03.005

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：152 / 161

页数：10

共 54 条

[1] Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum [J].