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

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. WenH. 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

Research output: Contribution to journalArticle

148 Citations (Scopus)

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. Significa nce: 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.

Original languageEnglish
Pages (from-to)442-456
Number of pages15
JournalCancer Discovery
Volume1
Issue number5
DOIs
Publication statusPublished - 2011 Oct
Externally publishedYes

Fingerprint

Sterol Regulatory Element Binding Protein 1
LDL Receptors
Glioblastoma
Epidermal Growth Factor Receptor
Cell Death
1-Phosphatidylinositol 4-Kinase
Cholesterol
Neoplasms
Survival
Liver X Receptors
Lipogenesis
Heterografts
Brain Neoplasms
Protein-Tyrosine Kinases
Homeostasis
Up-Regulation
Therapeutics

ASJC Scopus subject areas

  • Oncology

Cite this

Guo, D., Reinitz, F., Youssef, M., Hong, C., Nathanson, D., Akhavan, D., ... Mischel, P. S. (2011). An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/ SREBP-1/LDLR-dependent pathway. Cancer Discovery, 1(5), 442-456. https://doi.org/10.1158/2159-8290.CD-11-0102

An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/ SREBP-1/LDLR-dependent pathway. / 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.; Ian Robins, H.; Prados, Michael D.; DeAngelis, Lisa M.; Mellinghoff, Ingo K.; Mehta, Minesh P.; David James, C.; Chakravarti, Arnab; Cloughesy, Timothy F.; Tontonoz, Peter; Mischel, Paul S.

In: Cancer Discovery, Vol. 1, No. 5, 10.2011, p. 442-456.

Research output: Contribution to journalArticle

Guo, D, Reinitz, F, Youssef, M, Hong, C, Nathanson, D, Akhavan, D, Kuga, D, Amzajerdi, AN, Soto, H, Zhu, S, Babic, I, Tanaka, K, Dang, J, Iwanami, A, Gini, B, DeJesus, J, Lisiero, DD, Huang, TT, Prins, RM, Wen, PY, Ian Robins, H, Prados, MD, DeAngelis, LM, Mellinghoff, IK, Mehta, MP, David James, C, Chakravarti, A, Cloughesy, TF, Tontonoz, P & Mischel, PS 2011, 'An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/ SREBP-1/LDLR-dependent pathway', Cancer Discovery, vol. 1, no. 5, pp. 442-456. https://doi.org/10.1158/2159-8290.CD-11-0102
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. ; Ian Robins, H. ; Prados, Michael D. ; DeAngelis, Lisa M. ; Mellinghoff, Ingo K. ; Mehta, Minesh P. ; David James, C. ; Chakravarti, Arnab ; Cloughesy, Timothy F. ; Tontonoz, Peter ; Mischel, Paul S. / An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/ SREBP-1/LDLR-dependent pathway. In: Cancer Discovery. 2011 ; Vol. 1, No. 5. pp. 442-456.
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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. Significa nce: 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.",
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T1 - An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/ SREBP-1/LDLR-dependent pathway

AU - Guo, Deliang

AU - Reinitz, Felicia

AU - Youssef, Mary

AU - Hong, Cynthia

AU - Nathanson, David

AU - Akhavan, David

AU - Kuga, Daisuke

AU - Amzajerdi, Ali Nael

AU - Soto, Horacio

AU - Zhu, Shaojun

AU - Babic, Ivan

AU - Tanaka, Kazuhiro

AU - Dang, Julie

AU - Iwanami, Akio

AU - Gini, Beatrice

AU - DeJesus, Jason

AU - Lisiero, Dominique D.

AU - Huang, Tiffany T.

AU - Prins, Robert M.

AU - Wen, Patrick Y.

AU - Ian Robins, H.

AU - Prados, Michael D.

AU - DeAngelis, Lisa M.

AU - Mellinghoff, Ingo K.

AU - Mehta, Minesh P.

AU - David James, C.

AU - Chakravarti, Arnab

AU - Cloughesy, Timothy F.

AU - Tontonoz, Peter

AU - Mischel, Paul S.

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