Catabolic mediators of cancer cachexia

Abstract

Purpose of review: This review compares the catabolic actions of tumour necrosis factor-alpha (TNF-alpha) and proteolysis-inducing factor (PIF) and their involvement in human cancer cachexia.

Recent findings: TNF-alpha has a direct catabolic effect on skeletal muscle and adipose tissue, whereas PIF only has an effect on skeletal muscle. Both produce muscle atrophy through a depression of protein synthesis and an increase in protein degradation through the ubiquitin-proteasome proteolytic pathway, and this involves formation of reactive oxygen species leading to upregulation of the transcription factor nuclear factor-kappaB (NF-kappaB). TNF-alpha depresses protein synthesis through decreased phosphorylation of eukaryotic initiation factor-4E (eIF4E) binding protein (4E-BP1) leading to increased binding of eIF4E and a reduction in the active eIF4F complex, whereas with PIF depression of protein synthesis is due to an increased phosphorylation of eIF2 on the alpha-subunit. In general, serum levels of TNF-alpha do not correlate with weight loss in cancer patients and attempts to treat cachexia by interfering with TNF-alpha production, or action, have not been successful. Most studies show that PIF is detectable in the urine of cachectic cancer patients and its presence is indicative of weight loss. It is best to confirm that the band on Western blotting is PIF using both antibodies to the core peptide and the oligosaccharide chains.

Summary: These results suggest that blocking the PIF receptor or signalling pathways in skeletal muscle might yield new types of agents for the treatment of cancer cachexia.