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

• Published in: Cancer cell Vol. 19; no. 5; pp. 613 - 628
• Main Authors: Sheen, Joon-Ho, Zoncu, Roberto, Kim, Dohoon, Sabatini, David M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.05.2011
• Subjects: Animals; Antineoplastic Agents - pharmacology; Autophagy - drug effects; Autophagy - genetics; Caspase 3 - metabolism; Cell Line, Tumor; Chloroquine - pharmacology; Humans; Leucine - deficiency; Mechanistic Target of Rapamycin Complex 1; Melanocytes - drug effects; Melanocytes - metabolism; Melanocytes - pathology; Melanoma - diet therapy; Melanoma - drug therapy; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Mice; Mice, Nude; Mitochondria - metabolism; Mitogen-Activated Protein Kinase Kinases - metabolism; Multiprotein Complexes; Proteins - metabolism; ras Proteins - metabolism; RNA Interference; Signal Transduction; Time Factors; TOR Serine-Threonine Kinases; Transfection; Tumor Burden; Xenograft Model Antitumor Assays
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2011.03.012

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. [Display omitted] ► Defective autophagy upon leucine deprivation reveals a liability of melanoma cells ► Leucine deprivation triggers caspase activation and apoptosis of melanoma cells ► mTORC1 and MAPK pathways determine the sensitivity to leucine deprivation ► Dietary leucine deprivation and chloroquine synergistically induce apoptosis in vivo