Cancer cachexia is a multifactorial syndrome affecting the skeletal muscle. Previous clinical trials showed MEK inhibitor selumetinib treatment resulted in skeletal muscle anabolism. However, it is conflicting that MAPK/ERK pathway control mass of skeletal muscle. The present study investigated the therapeutic effect and mechanisms of selumetinib in amelioration of cancer cachexia. The classical cancer cachexia model was established via transplantation of CT26 colon adenocarcinoma into BALB/c mice. The effect of selumetinib on body weight, tumor growth, skeletal muscle, food intake, serum proinflammatory cytokines, E3 ligases and MEK/ERK-related pathways was analyzed. Two independent experiments showed that 30 mg/kg/d selumetinib prevented the loss of body weight in a murine cachexia mice. Muscle wasting was attenuated and the expression of E3 ligases MuRF1 and Fbx32 were inhibited following selumetinib treatment of muscle gastrocnemius. Further, selumetinib efficiently reduced tumor burden without influencing the cancer cell proliferation, cumulative food intake and serum cytokines. These results indicated that the role of selumetinib in attenuating muscle wasting was independent of cancer burden. Detailed mechanism analysis revealed AKT and mTOR were activated, while ERK, FoxO3a and GSK3β were inhibited in selumetinib treated cachexia group. These indicated selumetinib effectively prevented skeletal muscle wasting in cancer cachexia model through ERK inhibition and AKT activation in muscle gastrocnemius via cross-inhibition. The study not only elucidated the mechanism of MEK/ERK inhibition in skeletal muscle anabolism, but also validated selumetinib therapy as an effective intervention against cancer cachexia.
- Received May 20, 2016.
- Revision received August 9, 2016.
- Accepted August 22, 2016.
- Copyright ©2016, American Association for Cancer Research.