title: Targeting protein synthesis in a Myc/mTOR-driven model of anorexia-cachexia syndrome delays its onset and prolongs survival.
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.
authors.affiliation: Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Francis
authors.initials: F
authors.lastname: Robert
authors.forename: John R
authors.initials: JR
authors.lastname: Mills
authors.forename: Aouod
authors.initials: A
authors.lastname: Agenor
authors.forename: Dantong
authors.initials: D
authors.lastname: Wang
authors.forename: Sergio
authors.initials: S
authors.lastname: DiMarco
authors.forename: Regina
authors.initials: R
authors.lastname: Cencic
authors.forename: Michel L
authors.initials: ML
authors.lastname: Tremblay
authors.forename: Imed Eddine
authors.initials: IE
authors.lastname: Gallouzi
authors.forename: Siegfried
authors.initials: S
authors.lastname: Hekimi
authors.forename: Simon S
authors.initials: SS
authors.lastname: Wing
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
mesh_terms: D000818:Animals; D000855:Anorexia / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D000970:Antineoplastic Agents / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D002100:Cachexia / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006248:Harringtonines / Q000494:pharmacology; D000077863:Homoharringtonine; D006801:Humans; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D013577:Syndrome; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D006248:Harringtonines; D016271:Proto-Oncogene Proteins c-myc; D016753:Interleukin-10; D000077863:Homoharringtonine; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus