Targeting protein synthesis in a Myc/mTOR-driven model of anorexia-cachexia syndrome delays its onset and prolongs survival

Cancer Res. 2012 Feb 1;72(3):747-56. doi: 10.1158/0008-5472.CAN-11-2739. Epub 2011 Dec 12.

Abstract

Anorexia-cachexia syndrome (ACS) is a major determinant of cancer-related death that causes progressive body weight loss due to depletion of skeletal muscle mass and body fat. Here, we report the development of a novel preclinical murine model of ACS in which lymphomas harbor elevated Myc and activated mTOR signaling. The ACS phenotype in this model correlated with deregulated expression of a number of cytokines, including elevated levels of interleukin-10 which was under the direct translational control of mTOR. Notably, pharmacologic intervention to impair protein synthesis restored cytokine production to near-normal levels, delayed ACS progression, and extended host survival. Together, our findings suggest a new paradigm to treat ACS by strategies which target protein synthesis to block the production of procachexic factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anorexia / genetics
  • Anorexia / metabolism*
  • Anorexia / prevention & control
  • Antineoplastic Agents / pharmacology
  • Body Weight / drug effects
  • Cachexia / genetics
  • Cachexia / metabolism*
  • Cachexia / prevention & control
  • Cell Line, Tumor
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Disease Models, Animal
  • Female
  • Harringtonines / pharmacology
  • Homoharringtonine
  • Humans
  • Interleukin-10 / blood
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism
  • Kaplan-Meier Estimate
  • Lymphoma / genetics
  • Lymphoma / metabolism
  • Lymphoma / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Biosynthesis / drug effects
  • Protein Biosynthesis / genetics
  • Protein Biosynthesis / physiology*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Sirolimus / pharmacology
  • Syndrome
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Antineoplastic Agents
  • Harringtonines
  • Proto-Oncogene Proteins c-myc
  • Interleukin-10
  • Homoharringtonine
  • TOR Serine-Threonine Kinases
  • Sirolimus