Oncotarget

Research Papers:

The ATF6 pathway of the ER stress response contributes to enhanced viability in glioblastoma

David Y.A. Dadey, Vaishali Kapoor, Arpine Khudanyan, Fumihiko Urano, Albert H. Kim, Dinesh Thotala and Dennis E. Hallahan _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2016; 7:2080-2092. https://doi.org/10.18632/oncotarget.6712

Metrics: PDF 1631 views  |   HTML 1907 views  |   ?  


Abstract

David Y.A. Dadey1,5, Vaishali Kapoor1, Arpine Khudanyan1, Fumihiko Urano2,3, Albert H. Kim4,7,8, Dinesh Thotala1,7 and Dennis E. Hallahan1,6,7,8

1 Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA

2 Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA

3 Department of Pathology, Washington University School of Medicine, St. Louis, MO, USA

4 Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA

5 Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO, USA

6 Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA

7 Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA

8 Hope Center, Washington University School of Medicine, St. Louis, MO, USA

Correspondence to:

Dennis E. Hallahan, email:

Keywords: ATF6, radioresistance, glioblastoma, ER-stress, GRP78

Received: June 24, 2015 Accepted: November 21, 2015Published: December 21, 2015

Abstract

Therapeutic resistance is a major barrier to improvement of outcomes for patients with glioblastoma. The endoplasmic reticulum stress response (ERSR) has been identified as a contributor to chemoresistance in glioblastoma; however the contributions of the ERSR to radioresistance have not been characterized. In this study we found that radiation can induce ER stress and downstream signaling associated with the ERSR. Induction of ER stress appears to be linked to changes in ROS balance secondary to irradiation. Furthermore, we observed global induction of genes downstream of the ERSR in irradiated glioblastoma. Knockdown of ATF6, a regulator of the ERSR, was sufficient to enhance radiation induced cell death. Also, we found that activation of ATF6 contributes to the radiation-induced upregulation of glucose regulated protein 78 (GRP78) and NOTCH1. Our results reveal ATF6 as a potential therapeutic target to enhance the efficacy of radiation therapy.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 6712