Defective Regulation of Autophagy upon Leucine Deprivation Reveals a Targetable Liability of Human Melanoma Cells In Vitro and In Vivo

• Main Authors: Sheen, Joon-Ho (Author), Zoncu, Roberto (Author), Kim, Dohoon (Author), Sabatini, David M (Author), Sabatini, David (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor), Whitehead Institute for Biomedical Research (Contributor), Koch Institute for Integrative Cancer Research at MIT (Contributor), Sabatini, David M. (Contributor)
• Format: Article
• Language: English
• Published: Elsevier, 2014-12-10T17:10:53Z.
• Subjects: Article
• Online Access: Get fulltext

Autophagy is of increasing interest as a target for cancer therapy. We find that leucine deprivation causes the caspase-dependent apoptotic death of melanoma cells because it fails to appropriately activate autophagy. Hyperactivation of the RAS-MEK pathway, which is common in melanoma, prevents leucine deprivation from inhibiting mTORC1, the main repressor of autophagy under nutrient-rich conditions. In an in vivo tumor xenograft model, the combination of a leucine-free diet and an autophagy inhibitor synergistically suppresses the growth of human melanoma tumors and triggers widespread apoptosis of the cancer cells. Together, our study represents proof of principle that anticancer effects can be obtained with a combination of autophagy inhibition and strategies to deprive tumors of leucine.
National Institutes of Health (U.S.) (Grant R01 CA103866)
National Institutes of Health (U.S.) (Grant CA1299105)