Enhancement of the BMP-Smad axis for the treatment of the wasting phenotype in cancer cachexia.

Cancer cachexia is a systemic condition characterized by unintended body weight loss, adipose tissue wasting, and skeletal muscle atrophy driven by systemic inflammation. Cachexia occurs in up to 80% of all cancer types, affecting patients’ life quality and worsening their prognosis and therapy responses, being the cause of death of at least 20% of cancer cases. Despite its high prevalence, due to the scarce knowledge on its molecular mechanism, cancer cachexia is still incurable and unmet medical need. In this study, we present data on the use of tacrolimus to prevent the cachectic condition in mice via the activation of BMP-Smad pathway. Tacrolimus (FK506) is a drug currently used as immunosuppressant to avoid transplant rejection. Despite this widely known mechanism, recent insights are demonstrating the protective effects of sub-immunosuppressive doses of tacrolimus in various organs, exploiting its pharmacological action on the BMP-Smad axis. Here, we showed that tacrolimus is able to induce C2C12 myotubes hypertrophy and to rescue Activin A and cancer cells conditioned medium-induced atrophy in vitro, enhancing BMP-Smad1/5/8 signaling, increasing protein synthesis, and reducing ubiquitin-driven protein degradation. Moreover, tacrolimus treatment prevents cancer-induced body weight loss and fat tissue wasting in cachectic colon-26 (C26) tumor bearing mice. Interestingly, tacrolimus is able to avoid skeletal muscle atrophy, reducing atrogenes expression, the gene signature of atrophic skeletal muscles. These findings demonstrate that tacrolimus is a promising treatment to rescue body weight loss, adipose tissue wasting, and skeletal muscle atrophy in cachectic tumor-bearing mice, thus holding a potential for preventing the wasting phenotype in cancer patients.