Abstract
Aims: At the time of diagnosis, 60% of lung cancer patients present with cachexia, a severe wasting syndrome that increases morbidity and mortality. Tumors secrete multiple factors that contribute to cachectic muscle wasting, and not all of these factors have been identified. We used Orbitrap electrospray ionization mass spectrometry to identify novel cachexia-inducing candidates in media conditioned with Lewis lung carcinoma cells (LCM). Results: One-hundred and 58 proteins were confirmed in three biological replicates. Thirty-three were identified as secreted proteins, including 14-3-3 proteins, which are highly conserved adaptor proteins known to have over 200 binding partners. We confirmed the presence of extracellular 14-3-3 proteins in LCM via western blot and discovered that LCM contained less 14-3-3 content than media conditioned with C2C12 myotubes. Using a neutralizing antibody, we depleted extracellular 14-3-3 proteins in myotube culture medium, which resulted in diminished myosin content. We identified the proposed receptor for 14-3-3 proteins, CD13, in differentiated C2C12 myotubes and found that inhibiting CD13 via Bestatin also resulted in diminished myosin content. Conclusions: Our novel findings show that extracellular 14-3-3 proteins may act as previously unidentified myokines and may signal via CD13 to help maintain muscle mass.
Highlights
Lung cancer kills more people each year than prostate, pancreatic, breast, and colon cancers combined (Society, 2012)
After 48 h of lung carcinoma cells (LCM) treatment, we found that the average width in control myotubes increased, while the average width in LCM-treated myotubes decreased (Figures 1A–C)
Our novel findings show that: extracellular 14-3-3 proteins have a role in muscle maintenance; CD13 is present on differentiated skeletal muscle; and CD13 may act as the receptor for 14-3-3 proteins
Summary
Lung cancer kills more people each year than prostate, pancreatic, breast, and colon cancers combined (Society, 2012). At the time of diagnosis, 60% of lung cancer patients have cachexia, a severe wasting syndrome that includes loss of muscle mass, weakness, and fatigue (Fox and Wang, 2007; Fearon et al, 2011; Society, 2012). This syndrome cannot be reversed by nutritional interventions, diminishes response to and tolerance of cancer treatments, and increases morbidity and mortality (Fearon et al, 2013). Tumor- and host-derived inflammatory factors stimulate degradation of myofibrillar proteins via signaling pathways, including up-regulation of ubiquitin proteasome activity and autophagy (Romanello and Sandri, 2010; Fearon et al, 2013).
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