Blocking the uptake of large amounts of cholesterol into brain cancer cells could provide a new strategy to battle glioblastoma, one of the most deadly malignancies, researchers at UCLA's Jonsson Comprehensive Cancer Center have found.
The study, done in cells lines, mouse models and analysis of tissue from brain cancer patients, uncovered a novel mechanism by which the most commonly activated oncogene, the mutated epidermal growth factor receptor (EGFR), overcomes normal cell regulatory mechanisms to feed large amounts of cholesterol to the brain cancer cells, said Dr. Paul Mischel, a professor of pathology and laboratory medicine and molecular and medical pharmacology, a Jonsson Cancer Center researcher and senior author of the study.
The study appears Sept. 15 in Cancer Discovery, the newest peer-reviewed journal of the American Association for Cancer Research. It shows that EGFRvIII, common in glioblastoma, promotes the import of cholesterol into cancer cells by up-regulating its cellular receptor, the LDL receptor, promoting rapid tumor growth and survival.
There are at least three ways by which cells normally tightly control their cholesterol levels - synthesis, import and efflux, or pumping out the cholesterol, Mischel said.
"Our study found that the mutant EGFR hijacks this system, enabling cancer cells to import large amounts of cholesterol through the LDL receptor," Mischel said. "This study identifies the LDL receptor as a key regulator of cancer cell growth and survival, and as a potential drug target."
Mischel and his colleagues hypothesized that targeting the LDL receptor for destruction could result in strong anti-tumor activity against glioblastoma. They showed that a drug that activates the nuclear Liver X Receptor, a critical regulator of intracellular cholesterol that ensures appropriately balanced levels, degraded the LDL receptor in tumor cells bearing EGFR mutations, potently killing
|Contact: Kim Irwin|
University of California - Los Angeles Health Sciences