Oncotarget

Research Papers:

ATF4 contributes to autophagy and survival in sunitinib treated brain tumor initiating cells (BTICs)

Sylvia Moeckel, Kelly LaFrance, Julia Wetsch, Corinna Seliger, Markus J. Riemenschneider, Martin Proescholdt, Peter Hau _ and Arabel Vollmann-Zwerenz

PDF  |  HTML  |  Supplementary Files  |  Order a Reprint

Oncotarget. 2019; 10:368-382. https://doi.org/10.18632/oncotarget.26569

Metrics: PDF 248 views  |   HTML 395 views  |   ?  


Abstract

Sylvia Moeckel1, Kelly LaFrance1, Julia Wetsch1, Corinna Seliger1, Markus J. Riemenschneider2, Martin Proescholdt3, Peter Hau1,* and Arabel Vollmann-Zwerenz1,*

1Wilhelm Sander-NeuroOncology Unit and Department of Neurology, Regensburg University Hospital, Regensburg, Germany

2Department of Neuropathology, Regensburg University Hospital, Regensburg, Germany

3Department of Neurosurgery, Regensburg University Hospital, Regensburg, Germany

*These authors contributed equally to this work

Correspondence to:

Peter Hau, email: peter.hau@ukr.de

Keywords: glioblastoma; brain tumor initiating cells; ATF4; therapy resistance; receptor-tyrosine-kinase-inhibitor

Received: August 13, 2017     Accepted: December 29, 2018     Published: January 08, 2019

ABSTRACT

Receptor tyrosine kinase (RTK) pathways are known to play an important role in tumor cell proliferation of glioblastoma (GBM). Cellular determinants of RTK-inhibitor sensitivity are important to optimize and tailor treatment strategies.

The stress response gene activating transcription factor 4 (ATF4) is involved in homeostasis and cellular protection. However, little is known about its function in GBM. We found that the ATF4/p-eIF2α pathway is activated in response to Sunitinib in primary tumor initiating progenitor cell cultures (BTICs). Furthermore, lysosome entrapment of RTK-inhibitors (RTK-Is) leads to accumulation of autophagosomes. In case of Sunitinib treated cells, autophagy is additionally increased by ATF4 mediated upregulation of autophagy genes. Inhibition of ATF4 by small interfering RNA (siRNA) reduced autophagy and cell proliferation after Sunitinib treatment in a subset of BTIC cultures.

Overall, this study suggests a pro-survival role of the ATF4/p-eIF2α pathway in a cell type and treatment specific manner.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 26569