title: An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway.
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.
authors: Department of Radiation Oncology, Arthur G. James Comprehensive Cancer Center, The Ohio State University Medical School, Columbus, OH, USA.
authors: Deliang
authors: D
authors: Guo
authors: Felicia
authors: F
authors: Reinitz
authors: Mary
authors: M
authors: Youssef
authors: Cynthia
authors: C
authors: Hong
authors: David
authors: D
authors: Nathanson
authors: David
authors: D
authors: Akhavan
authors: Daisuke
authors: D
authors: Kuga
authors: Ali Nael
authors: AN
authors: Amzajerdi
authors: Horacio
authors: H
authors: Soto
authors: Shaojun
authors: S
authors: Zhu
authors: Ivan
authors: I
authors: Babic
authors: Kazuhiro
authors: K
authors: Tanaka
authors: Julie
authors: J
authors: Dang
authors: Akio
authors: A
authors: Iwanami
authors: Beatrice
authors: B
authors: Gini
authors: Jason
authors: J
authors: Dejesus
authors: Dominique D
authors: DD
authors: Lisiero
authors: Tiffany T
authors: TT
authors: Huang
authors: Robert M
authors: RM
authors: Prins
authors: Patrick Y
authors: PY
authors: Wen
authors: H Ian
authors: HI
authors: Robins
authors: Michael D
authors: MD
authors: Prados
authors: Lisa M
authors: LM
authors: Deangelis
authors: Ingo K
authors: IK
authors: Mellinghoff
authors: Minesh P
authors: MP
authors: Mehta
authors: C David
authors: CD
authors: James
authors: Arnab
authors: A
authors: Chakravarti
authors: Timothy F
authors: TF
authors: Cloughesy
authors: Peter
authors: P
authors: Tontonoz
authors: Paul S
authors: PS
authors: Mischel
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects* / Q000235:genetics; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D000077341:Lapatinib; D000071518:Liver X Receptors; D051379:Mice; D016513:Mice, SCID; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D011799:Quinazolines / Q000627:therapeutic use; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; C573412:LDLR protein, human; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011799:Quinazolines; D011973:Receptors, LDL; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; C410723:epidermal growth factor receptor VIII; D000077341:Lapatinib; D002784:Cholesterol; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt