Cachexia is a highly debilitating syndrome affecting more than a half patients with advanced cancer. The major clinical feature of cachexia is severe muscle wasting leading to pronounced weight loss, impaired quality of life, reduced response to anti-cancer therapy and poor outcome. Although several molecules have been implicated in cancer-induced muscle wasting, cachexia remains an untreated and poorly understood process. RAGE (Receptor for Advanced Glycation End-products) and its physiological ligands, S100B and HMGB1, are involved in muscle regeneration, inflammation, and tumor growth, all of which represent key processes in cachexia. We found that RAGE, S100B and HMGB1 counteract atrophy induced by TNFα±IFNγ in myotubes in vitro and in muscles in vivo by interfering with the ubiquitin-proteasome system. However, excess RAGE ligands lead to myotube atrophy, and we detected high amounts of RAGE, S100B and HMGB1 in cachectic muscles, and elevated S100B levels in the serum of cachectic mice. Interestingly, LLC (Lewis Lung carcinoma) cells and cachectic muscles, which re-express RAGE, release high amounts of S100B and HMGB1. Finally, LLC-bearing RAGE-null mice show delayed tumor appearance, reduced loss of muscle mass and atrogenes expression, and dramatic increase of survival rate compared with LLC-bearing WT mice. Thus, RAGE, S100B and HMGB1, which have a role in restoring muscle homeostasis in physiological conditions [1,2], appear to concur to muscle wasting in cancer conditions due to increased RAGE expression/activity and expression levels of S100B and HMGB1. Thus, RAGE, S100B and/or HMGB1 might represent molecular targets in therapeutic strategies to prevent or counteract muscle atrophy in cancer patients. *Equally contributed to the present work. 1. Riuzzi F. et al. HMGB1–RAGE regulates muscle satellite cell homeostasis through p38-MAPK- and myogenin-dependent repression of Pax7 transcription. J Cell Sci 2012;125:1440-54. 2. Riuzzi F. et al. S100B engages RAGE or bFGF/FGFR1 in myoblasts depending on its own concentration and myoblast density. Implications for muscle regeneration. PLoS ONE 2012;7: e28700.
The receptor RAGE: a potential molecular target in cancer cachexia
CHIAPPALUPI, SARA;RIUZZI, Francesca;UTRIO LANFALONI, SABRINA;SALVADORI, LAURA;Sagheddu, Roberta;DONATO, Rosario Francesco;SORCI, Guglielmo
2017
Abstract
Cachexia is a highly debilitating syndrome affecting more than a half patients with advanced cancer. The major clinical feature of cachexia is severe muscle wasting leading to pronounced weight loss, impaired quality of life, reduced response to anti-cancer therapy and poor outcome. Although several molecules have been implicated in cancer-induced muscle wasting, cachexia remains an untreated and poorly understood process. RAGE (Receptor for Advanced Glycation End-products) and its physiological ligands, S100B and HMGB1, are involved in muscle regeneration, inflammation, and tumor growth, all of which represent key processes in cachexia. We found that RAGE, S100B and HMGB1 counteract atrophy induced by TNFα±IFNγ in myotubes in vitro and in muscles in vivo by interfering with the ubiquitin-proteasome system. However, excess RAGE ligands lead to myotube atrophy, and we detected high amounts of RAGE, S100B and HMGB1 in cachectic muscles, and elevated S100B levels in the serum of cachectic mice. Interestingly, LLC (Lewis Lung carcinoma) cells and cachectic muscles, which re-express RAGE, release high amounts of S100B and HMGB1. Finally, LLC-bearing RAGE-null mice show delayed tumor appearance, reduced loss of muscle mass and atrogenes expression, and dramatic increase of survival rate compared with LLC-bearing WT mice. Thus, RAGE, S100B and HMGB1, which have a role in restoring muscle homeostasis in physiological conditions [1,2], appear to concur to muscle wasting in cancer conditions due to increased RAGE expression/activity and expression levels of S100B and HMGB1. Thus, RAGE, S100B and/or HMGB1 might represent molecular targets in therapeutic strategies to prevent or counteract muscle atrophy in cancer patients. *Equally contributed to the present work. 1. Riuzzi F. et al. HMGB1–RAGE regulates muscle satellite cell homeostasis through p38-MAPK- and myogenin-dependent repression of Pax7 transcription. J Cell Sci 2012;125:1440-54. 2. Riuzzi F. et al. S100B engages RAGE or bFGF/FGFR1 in myoblasts depending on its own concentration and myoblast density. Implications for muscle regeneration. PLoS ONE 2012;7: e28700.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
