期刊
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
卷 42, 期 12, 页码 2019-2029出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2010.09.003
关键词
Autophagy; Androstenediol; Eukaryotic translational initiation factor 2 alpha; Malignant glioma; Protein kinase-like endoplasmic reticulum kinase
资金
- MCV Medical Center A.D. Williams Trust Funds
- James and Martha Betts Foundation
- SCDR Cancer Research Fund
In this study, we identified a mechanism by which the neuro-steroid, 5-androstene 3 beta,17 alpha diol (17 alpha-AED) induces autophagy in human malignant glioma cells and transformed fibroblasts. 17 alpha-AED treatment induced endoplasmic reticulum (ER) stress, identified by the partial activation of an unfolded protein response in T98G, U87MG, U251MG, LN-18, LN-229 and LN-Z308 glioma cell lines. In this regard, there were increased levels of CCAAT/enhancer-binding protein homologous protein (CHOP) and glucose-regulated protein of 78 kDa transcripts but no splicing of X-box-binding protein 1 mRNA or processing of activating transcription factor-6 in glioma cells treated with the neuro-steroid. 17 alpha-AED induced eukaryotic translational initiation factor 2 alpha (eIF2 alpha) phosphorylation in glioma cells which correlated with microtubule-associated protein-light chain 3 (LC3) conversion from LC3-I to -II. In transformed murine embryonic fibroblasts (MEFs) that are deficient of eIF2 alpha function or T98G glioma cells transfected with a dominant-negative eIF2 alpha construct, 17 alpha-AED induced LC3 conversion was significantly reduced as compared to control cells. Neuro-steroid treatment caused the activation of the eIF2 alpha kinase, protein kinase-like ER kinase (PERK) but not other eIF2 alpha kinases in glioma cells. Moreover, eIF2 alpha phosphorylation and LC3 conversion, in response to 17 alpha-AED treatment, was blocked in MEFs that lacked PERK activity. T98G cells transfected with a dominant-negative PERK construct exhibited an attenuated response to neuro-steroid treatment in terms of decreases in: eIF2 alpha activation; CHOP expression; the incidence of autophagy; and cytotoxicity. These results demonstrate that ER stress is linked to 17 alpha-AED induced autophagy by PERK/eIF2 alpha signaling in human malignant glioma cells and transformed fibroblasts. (C) 2010 Elsevier Ltd. All rights reserved.
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