Cancer is a recognized cause of the prominently reduced muscle mass known as cachexia. Inflammatory cytokines such as TNF-α, IL-1β, IL-6 and IFN-γ are main atrophy-inducing factors in cachexia causing excess catabolism of myofibrillary proteins.1 RAGE (Receptor for Advanced Glycation End-products) and its physiological ligands, S100B and HMGB1, are involved in muscle regeneration, inflammation, and tumor growth, which represent key processes in cancer cachexia.2,3 We found that: i) RAGE signaling has a trophic effect in myotubes in physiological conditions; ii) excess RAGE ligands leads to myotube atrophy; iii) high amounts of S100B and HMGB1 are found in cachectic muscles, and elevated levels of S100B are present in the serum of cachectic mice, likely released by tumor cells; iv) atrophying muscles re-express RAGE; v) RAGE, S100B and HMGB1 are involved in the mechanism through which TNFα±IFNγ induces atrophy in myotubes in vitro and in muscles in vivo; vi) Lewis lung carcinoma (LLC)-bearing RAGE-null (Ager‒/‒) mice show reduced loss of muscle mass and reduced atrogenes expression, and a dramatic increase in survival rate compared with LLC-bearing WT mice, likely due to reduced systemic inflammation, maintenance of spleen morphology and a different tumor-derived cytokine profile. Thus, increased expression/activity of RAGE and its ligands, S100B and HMGB1 at both systemic and muscle levels appears to concur to muscle wasting in cancer conditions. References: 1. Porporato P.E., 2016, Oncogenesis. 22(5): e200; 2. Riuzzi F. et al., 2012, J. Cell Sci. 125:1440-54; 3. Riuzzi F. et al., 2012, PLoS ONE 7(1): e28700.
RAGE and its ligands, S100B and HMGB1, are molecular determinants of cancer-induced muscle wasting.
Chiappalupi S.;Riuzzi F.;Salvadori L.;Sagheddu R.;Donato R.;Sorci G.
2017
Abstract
Cancer is a recognized cause of the prominently reduced muscle mass known as cachexia. Inflammatory cytokines such as TNF-α, IL-1β, IL-6 and IFN-γ are main atrophy-inducing factors in cachexia causing excess catabolism of myofibrillary proteins.1 RAGE (Receptor for Advanced Glycation End-products) and its physiological ligands, S100B and HMGB1, are involved in muscle regeneration, inflammation, and tumor growth, which represent key processes in cancer cachexia.2,3 We found that: i) RAGE signaling has a trophic effect in myotubes in physiological conditions; ii) excess RAGE ligands leads to myotube atrophy; iii) high amounts of S100B and HMGB1 are found in cachectic muscles, and elevated levels of S100B are present in the serum of cachectic mice, likely released by tumor cells; iv) atrophying muscles re-express RAGE; v) RAGE, S100B and HMGB1 are involved in the mechanism through which TNFα±IFNγ induces atrophy in myotubes in vitro and in muscles in vivo; vi) Lewis lung carcinoma (LLC)-bearing RAGE-null (Ager‒/‒) mice show reduced loss of muscle mass and reduced atrogenes expression, and a dramatic increase in survival rate compared with LLC-bearing WT mice, likely due to reduced systemic inflammation, maintenance of spleen morphology and a different tumor-derived cytokine profile. Thus, increased expression/activity of RAGE and its ligands, S100B and HMGB1 at both systemic and muscle levels appears to concur to muscle wasting in cancer conditions. References: 1. Porporato P.E., 2016, Oncogenesis. 22(5): e200; 2. Riuzzi F. et al., 2012, J. Cell Sci. 125:1440-54; 3. Riuzzi F. et al., 2012, PLoS ONE 7(1): e28700.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
