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

// Sylvia Moeckel 1 , Kelly LaFrance 1 , Julia Wetsch 1 , Corinna Seliger 1 , Markus J. Riemenschneider 2 , Martin Proescholdt 3 , Peter Hau 1, * and Arabel Vollmann-Zwerenz 1, * 1 Wilhelm Sander-NeuroOncology Unit and Department of Neurology, Regensburg University Hospital, Regensburg, Germany 2 Department of Neuropathology, Regensburg University Hospital, Regensburg, Germany 3 Department 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.