Role of Transsignaling Molecules from Lewis Lung Carcinoma (LLC) Cells on C2C12 Myotube Atrophy and Protein Turnover Regulation
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abstract
Cancer cachexia is a metabolic wasting syndrome observed in many cancer patients that is characterized by unintentional body weight loss. Imbalances in rates of protein synthesis and degradation are responsible for cancerinduced skeletal muscle wasting. Lewis lung carcinoma (LLC) cell implantation is a widely used explant mouse model for examining cancer cachexia and muscle wasting. The purpose of this study is to investigate the influence of transsignals induced by LLC tumor cells on C2C12 myotube morphology and protein turnover regulation. C2C12 myotubes were treated with LLC cell culture medium (0%, 15% and 25%) for 4h, 24h and 72h. LLC medium treatment (25% for 72h) significantly decreased myotube diameter. The LLC medium induced both Stat3 and AMPK phosphorylation, while decreasing mTOR (S2448) and 4EBP1 (T37/46) phosphorylation in dose dependent manner. In addition, LLC treatment activated the FOXO3/Atrogin1 protein degradation signaling pathway. These results demonstrate that transsignaling molecules from LLC tumor cells can result in C2C12 myotube atrophy by both inhibiting mTOR regulation of protein synthesis pathway and activating protein degradation. (RO1CA121249)
