Defective regulation of autophagy upon leucine deprivation reveals a targetable liability of human melanoma cells in vitro and in vivo

Cancer Cell. 2011 May 17;19(5):613-28. doi: 10.1016/j.ccr.2011.03.012.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 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
  • RNA Interference
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Time Factors
  • Transfection
  • Tumor Burden
  • Xenograft Model Antitumor Assays
  • ras Proteins / metabolism

Substances

  • Antineoplastic Agents
  • Multiprotein Complexes
  • Proteins
  • Chloroquine
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Mitogen-Activated Protein Kinase Kinases
  • CASP3 protein, human
  • Caspase 3
  • ras Proteins
  • Leucine