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.
©2011 AACR.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anorexia / genetics
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Anorexia / metabolism*
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Anorexia / prevention & control
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Antineoplastic Agents / pharmacology
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Body Weight / drug effects
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Cachexia / genetics
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Cachexia / metabolism*
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Cachexia / prevention & control
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Cell Line, Tumor
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Colonic Neoplasms / genetics
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / pathology
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Disease Models, Animal
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Female
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Harringtonines / pharmacology
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Homoharringtonine
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Humans
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Interleukin-10 / blood
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Interleukin-10 / genetics
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Interleukin-10 / metabolism
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Kaplan-Meier Estimate
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Lymphoma / genetics
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Lymphoma / metabolism
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Lymphoma / pathology
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Protein Biosynthesis / drug effects
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Protein Biosynthesis / genetics
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Protein Biosynthesis / physiology*
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Signal Transduction / physiology
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Sirolimus / pharmacology
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Syndrome
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism*
Substances
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Antineoplastic Agents
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Harringtonines
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Proto-Oncogene Proteins c-myc
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Interleukin-10
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Homoharringtonine
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TOR Serine-Threonine Kinases
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Sirolimus