Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 10, Pages 4764-4769Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0910872107
Keywords
angiogenesis; cholesterol homeostasis; itraconazole
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Funding
- National Cancer Institute
- Flight Attendant Medical Research Institute
- Clinical and Translational Science Award
- Keck Foundation
- Patrick C. Walsh Prostate Cancer Research Fund
- Commonwealth Foundation
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Mammalian target of rapamycin (mTOR) constitutes a nodal point of a signaling network that regulates cell growth and proliferation in response to various environmental cues ranging from growth factor stimulation to nutrients to stress. Whether mTOR is also affected by cholesterol homeostasis, however, has remained unknown. We report that blockade of cholesterol trafficking through lysosome by a newly identified inhibitor of angiogenesis, itraconazole, leads to inhibition of mTOR activity in endothelial cells. Inhibition of mTOR by itraconazole but not rapamycin can be partially restored by extracellular cholesterol delivered by cyclodextrin. Moreover, other known inhibitors of endosomal/lysosomal cholesterol trafficking as well as siRNA knockdown of Niemann-Pick disease type C (NPC) 1 and NPC2 also cause inhibition of mTOR in endothelial cells. In addition, both the accumulation of cholesterol in the lysosome and inhibition of mTOR caused by itraconazole can be reversed by thapsigarin. These observations suggest that mTOR is likely to be involved in sensing membrane sterol concentrations in endothelial cells, and the cholesterol trafficking pathway is a promising target for the discovery of inhibitors of angiogenesis.
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