An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway

• Published in: Cancer discovery Vol. 1; no. 5; p. 442
• Main Authors: Guo, Deliang, Reinitz, Felicia, Youssef, Mary, Hong, Cynthia, Nathanson, David, Akhavan, David, Kuga, Daisuke, Amzajerdi, Ali Nael, Soto, Horacio, Zhu, Shaojun, Babic, Ivan, Tanaka, Kazuhiro, Dang, Julie, Iwanami, Akio, Gini, Beatrice, Dejesus, Jason, Lisiero, Dominique D, Huang, Tiffany T, Prins, Robert M, Wen, Patrick Y, Robins, H Ian, Prados, Michael D, Deangelis, Lisa M, Mellinghoff, Ingo K, Mehta, Minesh P, James, C David, Chakravarti, Arnab, Cloughesy, Timothy F, Tontonoz, Peter, Mischel, Paul S
• Format: Journal Article
• Language: English
• Published: United States 01-10-2011
• Subjects: Animals; ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell Death - drug effects; Cell Death - genetics; Cholesterol - genetics; Cholesterol - metabolism; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; HeLa Cells; Humans; Liver X Receptors; Mice; Mice, SCID; Orphan Nuclear Receptors - agonists; Orphan Nuclear Receptors - genetics; Orphan Nuclear Receptors - metabolism; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Quinazolines - therapeutic use; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Receptors, LDL - genetics; Receptors, LDL - metabolism; Signal Transduction - drug effects; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; Up-Regulation - drug effects
• ISSN: 2159-8290
• DOI: 10.1158/2159-8290.cd-11-0102

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.