Uncontrolled Cholesterol Synthesis Stimulates Growth of Glioblastoma

Studies on the physiology of glioblastoma cells have found that active tumors are able to circumvent the normal molecular mechanisms that control cholesterol synthesis in order to provide large quantities of this critical cell membrane component for the rapidly reproducing cancer cells.

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 overactive phosphoinositide 3-kinase (PI3K) are common in GBM. These mutations cause regulatory errors that promote tumor growth and survival, including sterol regulatory element-binding protein 1 (SREBP-1)–dependent lipid synthesis. EGFRvIII is a recognized oncogene in glioblastoma, which stimulates LDL receptor (LDLR) activity and promotes synthesis of large amounts of cholesterol.

Investigators at the University of California, Los Angeles (USA) worked with GBM cell lines, xenograft models, and GBM clinical samples, including those from patients treated with the EGFR tyrosine kinase inhibitor lapatinib. They reported in the September 15, 2011, online edition of the journal Cancer Discovery 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.

Treating GBM xenograph animals with the liver X receptor (LXR) agonist drug GW3965, which targets liver LDLR, caused LDLR degradation, and it increased expression of the ABCA1 cholesterol efflux transporter, with the effect of potently promoting tumor cell death. These results show that EGFRvIII promoted GBM tumor survival through PI3K/SREBP-1–dependent upregulation of LDLR and suggest a role for LXR agonists in the treatment of GBM patients.

“Our data demonstrate that glioblastoma cells need large amounts of cholesterol to grow and to survive. This is not surprising considering the critical role of cholesterol in making new membranes, of which rapidly growing tumors need a lot,” said senior author Dr. Paul Mischel, professor of molecular and medical pharmacology at the University of California, Los Angeles. “New treatments are needed. This study uncovers a novel and potentially therapeutically targetable tumor cell growth and survival pathway, which could potentially lead to more effective treatments for patients in the clinic. Pharmacologic strategies that pump cholesterol out of a cell could lead to significant tumor cell death.”

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