Knockdown of Amphiregulin Triggers Doxorubicin-Induced Autophagic and Apoptotic Death by Regulating Endoplasmic Reticulu
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Knockdown of Amphiregulin Triggers Doxorubicin-Induced Autophagic and Apoptotic Death by Regulating Endoplasmic Reticulum Stress in Glioblastoma Cells I-Neng Lee 1 & Jen-Tsung Yang 2,3 & Ming-Ju Hsieh 4,5,6,7 & Cheng Huang 8,9 & Hsiu-Chen Huang 10 & Yu-Ju Ku 11 & Yu-Ping Wu 3 & Kuan-Chieh Huang 12 & Jui-Chieh Chen 12 Received: 1 November 2019 / Accepted: 15 May 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Glioblastoma multiforme (GBM) is the most common type of malignant brain tumor. The present standard treatment for GBM has not been effective; therefore, the prognosis remains dramatically poor and prolonged survival after treatment is still limited. The new therapeutic strategies are urgently needed to improve the treatment efficiency. Doxorubicin (Dox) has been widely used in the treatment of many cancers for decades. In recent years, with the advancement of delivery technology, more and more research indicates that Dox has the opportunity to be used in the treatment of GBM. Amphiregulin (AREG), a ligand of the epidermal growth factor receptor (EGFR), has been reported to have oncogenic effects in many cancer cell types and is implicated in drug resistance. However, the biological function and molecular mechanism of AREG in Dox treatment of GBM are still unclear. Here, we demonstrate that knockdown of AREG can boost Dox-induced endoplasmic reticulum (ER) stress to trigger activation in both autophagy and apoptosis in GBM cells, ultimately leading to cell death. To explore the importance of AREG in the clinic, we used available bioinformatics tools and found AREG is highly expressed in GBM tumor tissues that are associated with poor survival. In addition, we also used antibody array analysis to dissect pathways that are likely to be activated by AREG. Taken together, our results revealed AREG can serve as a potential therapeutic target and a promising biomarker in GBM. Keywords Amphiregulin . Glioblastoma multiforme (GBM) . Doxorubicin . Drug resistance . Endoplasmic reticulum (ER) stress . Autophagy
Introduction Glioblastoma multiforme (GBM) is an astrocytic tumor that is classified as a grade IV by the World Health Organization
(Wesseling and Capper 2018). It is one of the most common and lethal forms of malignant primary brain tumor. The standard strategies for clinical treatment of GBM are the surgical resection, radiotherapy, and adjuvant chemotherapy.
* Jui-Chieh Chen [email protected]
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Department of Holistic Wellness, Mingdao University, Changhua 52345, Taiwan
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Department of Medical Research, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan
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Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei 112, Taiwan
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Department of Neurosurgery, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan
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Department of Earth and Life Sciences, University of Taipei, Taipei 100, Taiwan
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Department of Applied Science, National Tsing Hua University, South Campus, No. 521, Nanda Road, Hsinchu 30014, Taiwan
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The Cen
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