Mechanical stretch can activate muscle and myotube protein synthesis through mTORC1 signaling. While it has been established that tumor-derived cachectic factors can induce myotube wasting, the effect of this catabolic environment on myotube mechanical signaling has not been determined. We investigated if media containing cachectic factors derived from Lewis Lung Carcinoma (LLC) can regulate the stretch induction of myotube protein synthesis. C2C12 myotubes pre-incubated in control or LLC-derived media were chronically stretched. Protein synthesis regulation by anabolic and catabolic signaling was then examined. In the control condition, stretch increased mTORC1 activity and protein synthesis. The LLC treatment decreased basal mTORC1 activity and protein synthesis and attenuated the stretch induction of protein synthesis. LLC media increased STAT3 and AMPK phosphorylation in myotubes independent of stretch. Both stretch and LLC independently increased ERK1/2, p38 and NF-B phosphorylation. In LLC-treated myotubes, the inhibition of ERK1/2 and p38 rescued the stretch induction of protein synthesis. Interestingly, either LIF or gp130 antibody administration caused further inhibition of mTORC1 signaling and protein synthesis in stretched myotubes. AMPK inhibition increased basal mTORC1 signaling activity and protein synthesis in LLC-treated myotubes, but did not restore the stretch induction of protein synthesis. These results demonstrate that LLC-derived cachectic factors can dissociate stretch-induced signaling from protein synthesis through ERK1/2 and p38 signaling, and that gp130 signaling is associated with the basal stretch response in myotubes.