Data from An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway
Year: 2023
Type: other
Abstract: Glioblastoma (GBM) is the most common malignant primary brain tumor of adults and one of the most lethal of all cancers. Epidermal growth factor receptor (EGFR) mutations (EGFRvIII) and phosphoinositide 3-kinase (PI3K) hyperactivation are common in GBM, promoting tumor growth and survival, including through sterol regulatory element-binding protein 1 (SREBP-1)–dependent lipogenesis. The role of cholesterol metabolism in GBM pathogenesis, its association with EGFR/PI3K signaling, and its potential therapeutic targetability are unknown. In our investigation, studies of GBM cell lines, xenograft models, and GBM clinical samples, including those from patients treated with the EGFR tyrosine kinase inhibitor lapatinib, uncovered an EGFRvIII-activated, PI3K/SREBP-1–dependent tumor survival pathway through the low-density lipoprotein receptor (LDLR). Targeting LDLR with the liver X receptor (LXR) agonist GW3965 caused inducible degrader of LDLR (IDOL)–mediated LDLR degradation and increased expression of the ABCA1 cholesterol efflux transporter, potently promoting tumor cell death in an in vivo GBM model. These results show that EGFRvIII can promote tumor survival through PI3K/SREBP-1–dependent upregulation of LDLR and suggest a role for LXR agonists in the treatment of GBM patients. Significance: This study reveals that GBM cells have devised a mechanism to subvert the normal pathways for feedback inhibition of cholesterol homeostasis via EGFRvIII and PI3K-dependent activation of SREBP-1. We show that an LXR agonist causes IDOL-mediated LDLR degradation and increases expression of the ABCA1 cholesterol efflux transporter, potently promoting GBM cell death in vivo. These results suggest a role for LXR agonists in the treatment of GBM patients. Cancer Discovery; 1(5): 442–56. ©2011 AACR. Read the Commentary on this article by Moschetta, p. 381 This article is highlighted in the In This Issue feature, p. 367
Authors: Deliang Guo, Felicia Reinitz, Mary Youssef, Cynthia Hong, David Nathanson, David Akhavan, Daisuke Kuga, Ali Nael Amzajerdi, Horacio Soto, Shaojun Zhu, Ivan Babic, Kazuhiro Tanaka, Julie Dang, Akio Iwanami, Beatrice Gini, Jason DeJesus, Dominique D. Lisiero, Tiffany T. Huang, Robert M. Prins, Patrick Y. Wen, H. Ian Robins, Michael D. Prados, Lisa M. DeAngelis, Ingo K. Mellinghoff, Minesh P. Mehta, C. David James, Arnab Chakravarti, Timothy F. Cloughesy, Peter Tontonoz, Paul S. Mischel
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4362483851