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

   

Authors:	Guo, D. L.; Reinitz, F.; Youssef, M.; Hong, C.; Nathanson, D.; Akhavan, D.; Kuga, D.; Amzajerdi, A. N.; Soto, H.; Zhu, S. J.; Babic, I.; Tanaka, K.; Dang, J. L.; Iwanami, A.; Gini, B.; DeJesus, J.; Lisiero, D. D.; Huang, T. T.; Prins, R. M.; Wen, P. Y.; Robins, H. I.; Prados, M. D.; Deangelis, L. M.; Mellinghoff, I. K.; Mehta, M. P.; James, C. D.; Chakravarti, A.; Cloughesy, T. F.; Tontonoz, P.; Mischel, P. S.
Article 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. 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. (C) 2011 AACR.
Keywords:	in-vivo; prostate-cancer; growth-factor receptor; nuclear; receptors; lipid rafts; protein-kinase; signaling pathway; kinase inhibitors; fatty-acid synthase; ldl receptor
Journal Title:	Cancer Discovery
Volume:	1
Issue:	5
ISSN:	2159-8274
Publisher:	American Association for Cancer Research
Date Published:	2011-09-15
Start Page:	442
End Page:	456
Language:	English
ACCESSION:	WOS:000296140600022
DOI:	10.1158/2159-8290.cd-11-0102
PROVIDER:	wos
PMCID:	PMC3207317
PUBMED:	22059152
Notes:	--- - Article - "Source: Wos"

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