Targeting cholesterol metabolism in glioblastoma: A new therapeutic approach in cancer therapy

Leila Pirmoradi, Nayer Seyfizadeh, Saeid Ghavami, Amir Zeki, Shahla Shojaei

Research output: Contribution to journalReview article

7 Citations (Scopus)

Abstract

Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor known with a poor survival rate despite current advances in the field of cancer. Additional research into the pathophysiology of GBM is urgently needed given the devastating nature of this disease. Recent studies have revealed the unique cellular physiology of GBM cells as compared with healthy astrocytes. Intriguingly, GBM cells are incapable of de novo cholesterol synthesis via the mevalonate pathway. Thus, the survival of GBM cells depends on cholesterol uptake via low-density lipoprotein receptors (LDLRs) in the form of apolipoprotein-E-containing lipoproteins and ATP-binding cassette transporter A1 (ABCA1) that efflux surplus cholesterol out of cells. Liver X receptors regulate intracellular cholesterol levels in neurons and healthy astrocytes through changes in the expression of LDLR and ABCA1 in response to cholesterol and its derivatives. In GBM cells, due to the dysregulation of this surveillance pathway, there is an accumulation of intracellular cholesterol. Furthermore, intracellular cholesterol regulates temozolomide-induced cell death in glioblastoma cells via accumulation and activation of death receptor 5 in plasma membrane lipid rafts. The mevalonate pathway and autophagy flux are also fundamentally related with implications for cell health and death. Thus, via cholesterol metabolism, the mevalonate pathway may be a crucial player in the pathogenesis and treatment of GBM where our current understanding is still lacking. Targeting cholesterol metabolism in GBM may hold promise as a novel adjunctive clinical therapy for this devastating cancer.

Original languageEnglish (US)
JournalJournal of Investigative Medicine
DOIs
StatePublished - Jan 1 2019

Fingerprint

Glioblastoma
Metabolism
Cholesterol
Neoplasms
Mevalonic Acid
ATP-Binding Cassette Transporters
Therapeutics
LDL Receptors
temozolomide
Astrocytes
Cell Death
TNF-Related Apoptosis-Inducing Ligand Receptors
Autophagy
Physiology
Apolipoproteins E
Cell death
Cell membranes
Membrane Lipids
Brain Neoplasms
Liver

Keywords

  • Brain
  • Mevalonate pathway
  • Tumour

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Targeting cholesterol metabolism in glioblastoma : A new therapeutic approach in cancer therapy. / Pirmoradi, Leila; Seyfizadeh, Nayer; Ghavami, Saeid; Zeki, Amir; Shojaei, Shahla.

In: Journal of Investigative Medicine, 01.01.2019.

Research output: Contribution to journalReview article

@article{d9c813e4da2440119f8fe4965d552c93,
title = "Targeting cholesterol metabolism in glioblastoma: A new therapeutic approach in cancer therapy",
abstract = "Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor known with a poor survival rate despite current advances in the field of cancer. Additional research into the pathophysiology of GBM is urgently needed given the devastating nature of this disease. Recent studies have revealed the unique cellular physiology of GBM cells as compared with healthy astrocytes. Intriguingly, GBM cells are incapable of de novo cholesterol synthesis via the mevalonate pathway. Thus, the survival of GBM cells depends on cholesterol uptake via low-density lipoprotein receptors (LDLRs) in the form of apolipoprotein-E-containing lipoproteins and ATP-binding cassette transporter A1 (ABCA1) that efflux surplus cholesterol out of cells. Liver X receptors regulate intracellular cholesterol levels in neurons and healthy astrocytes through changes in the expression of LDLR and ABCA1 in response to cholesterol and its derivatives. In GBM cells, due to the dysregulation of this surveillance pathway, there is an accumulation of intracellular cholesterol. Furthermore, intracellular cholesterol regulates temozolomide-induced cell death in glioblastoma cells via accumulation and activation of death receptor 5 in plasma membrane lipid rafts. The mevalonate pathway and autophagy flux are also fundamentally related with implications for cell health and death. Thus, via cholesterol metabolism, the mevalonate pathway may be a crucial player in the pathogenesis and treatment of GBM where our current understanding is still lacking. Targeting cholesterol metabolism in GBM may hold promise as a novel adjunctive clinical therapy for this devastating cancer.",
keywords = "Brain, Mevalonate pathway, Tumour",
author = "Leila Pirmoradi and Nayer Seyfizadeh and Saeid Ghavami and Amir Zeki and Shahla Shojaei",
year = "2019",
month = "1",
day = "1",
doi = "10.1136/jim-2018-000962",
language = "English (US)",
journal = "Journal of Investigative Medicine",
issn = "1081-5589",
publisher = "Lippincott Williams and Wilkins",

}

TY - JOUR

T1 - Targeting cholesterol metabolism in glioblastoma

T2 - A new therapeutic approach in cancer therapy

AU - Pirmoradi, Leila

AU - Seyfizadeh, Nayer

AU - Ghavami, Saeid

AU - Zeki, Amir

AU - Shojaei, Shahla

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor known with a poor survival rate despite current advances in the field of cancer. Additional research into the pathophysiology of GBM is urgently needed given the devastating nature of this disease. Recent studies have revealed the unique cellular physiology of GBM cells as compared with healthy astrocytes. Intriguingly, GBM cells are incapable of de novo cholesterol synthesis via the mevalonate pathway. Thus, the survival of GBM cells depends on cholesterol uptake via low-density lipoprotein receptors (LDLRs) in the form of apolipoprotein-E-containing lipoproteins and ATP-binding cassette transporter A1 (ABCA1) that efflux surplus cholesterol out of cells. Liver X receptors regulate intracellular cholesterol levels in neurons and healthy astrocytes through changes in the expression of LDLR and ABCA1 in response to cholesterol and its derivatives. In GBM cells, due to the dysregulation of this surveillance pathway, there is an accumulation of intracellular cholesterol. Furthermore, intracellular cholesterol regulates temozolomide-induced cell death in glioblastoma cells via accumulation and activation of death receptor 5 in plasma membrane lipid rafts. The mevalonate pathway and autophagy flux are also fundamentally related with implications for cell health and death. Thus, via cholesterol metabolism, the mevalonate pathway may be a crucial player in the pathogenesis and treatment of GBM where our current understanding is still lacking. Targeting cholesterol metabolism in GBM may hold promise as a novel adjunctive clinical therapy for this devastating cancer.

AB - Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor known with a poor survival rate despite current advances in the field of cancer. Additional research into the pathophysiology of GBM is urgently needed given the devastating nature of this disease. Recent studies have revealed the unique cellular physiology of GBM cells as compared with healthy astrocytes. Intriguingly, GBM cells are incapable of de novo cholesterol synthesis via the mevalonate pathway. Thus, the survival of GBM cells depends on cholesterol uptake via low-density lipoprotein receptors (LDLRs) in the form of apolipoprotein-E-containing lipoproteins and ATP-binding cassette transporter A1 (ABCA1) that efflux surplus cholesterol out of cells. Liver X receptors regulate intracellular cholesterol levels in neurons and healthy astrocytes through changes in the expression of LDLR and ABCA1 in response to cholesterol and its derivatives. In GBM cells, due to the dysregulation of this surveillance pathway, there is an accumulation of intracellular cholesterol. Furthermore, intracellular cholesterol regulates temozolomide-induced cell death in glioblastoma cells via accumulation and activation of death receptor 5 in plasma membrane lipid rafts. The mevalonate pathway and autophagy flux are also fundamentally related with implications for cell health and death. Thus, via cholesterol metabolism, the mevalonate pathway may be a crucial player in the pathogenesis and treatment of GBM where our current understanding is still lacking. Targeting cholesterol metabolism in GBM may hold promise as a novel adjunctive clinical therapy for this devastating cancer.

KW - Brain

KW - Mevalonate pathway

KW - Tumour

UR - http://www.scopus.com/inward/record.url?scp=85061633076&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061633076&partnerID=8YFLogxK

U2 - 10.1136/jim-2018-000962

DO - 10.1136/jim-2018-000962

M3 - Review article

C2 - 30765502

AN - SCOPUS:85061633076

JO - Journal of Investigative Medicine

JF - Journal of Investigative Medicine

SN - 1081-5589

ER -