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Cancer Cachexia Signaling Pathways Continue to Emerge Yet Much Still Points to the Proteasome

Authors' Affiliation: Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics, Integrated Biomedical Graduate Program, The Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio

Requests for reprints: Denis C. Guttridge, Human Cancer Genetics, The Ohio State University College of Medicine, 420 West 12th Avenue, Columbus, OH 43210. Phone: 614-688-3137; Fax: 614-688-4006; E-mail: denis.guttridge{at}osumc.edu.

Cachexia is a life-threatening consequence of cancer that diminishes both quality of life and survival. It is a syndrome that is characterized by extreme weight loss resulting mainly from the depletion of skeletal muscle. Research from the past decades investigating the mechanisms of tumor-induced muscle wasting has identified several key cachectic factors that act through the ubiquitin-dependent proteasome system. Signaling pathways that mediate the effects of these cachectic factors have also subsequently emerged. Here, we review some of these pathways specific to myostatin, nuclear factor B, and the newly elucidated dystrophin glycoprotein complex. Although these molecules are likely to employ distinct modes of action, results suggest that they nevertheless maintain a link to the proteasome pathway. Therefore, although the proteasome remains a preferred choice for therapy, the continually emerging upstream signaling molecules serve as additional promising therapeutic targets for the treatment of tumor-induced muscle wasting.