• Exercise training prolongs lifespan, reduces oxidative stress, and improves skeletal muscle function in tumor-bearing rats. • Muscle COP9 signalosome complex subunit 2 (COPS2) protein is downregulated in cancer cachexia. • Exercise training restores COPS2 protein expression to control levels. • Cancer-conditioned media decreased F-actin expression in myotubes, which is partially restored by COPS2 knockdown. • COPS2 overexpression decreases DR4 activity and COPS2 knockdown inhibits cancer-conditioned media effects on DR4 activity.