Molecular Pathways: Cachexia Signaling-A Targeted Approach to Cancer Treatment

Abstract

Cancer cachexia is a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass, which negatively affects quality of life and portends a poor prognosis. Numerous molecular substrates and mechanisms underlie the dysregulation of skeletal muscle synthesis and degradation observed in cancer cachexia, including proinflammatory cytokines (TNFα, IL1, and IL6), and the NF-κB, IGF1/AKT/mTOR, and myostatin/activin-SMAD pathways. Recent preclinical and clinical studies have demonstrated that anti-cachexia drugs (such as MABp1 and soluble receptor antagonist of myostatin/activin) not only prevent muscle wasting but also may prolong overall survival. In this review, we focus on the significance of cachexia signaling in patients with cancer and highlight promising drugs targeting tumor cachexia in clinical development. Clin Cancer Res; 22(16); 3999-4004. ©2016 AACR.

Fig. 1. Cachexia signaling regulating protein synthesis and degradation in muscle and anti-cachexia drugs in development

IGF-Akt-mTOR signaling: Binding of IGF-1 to IGF-1R results in phosphorylation of the insulin receptor substrate (IRS). IRS activates PI3K-Akt signaling, which then stimulates protein synthesis by activating mTOR. mTOR activates the ribosomal S6K and eukaryotic initiation factor 4E-BP-1, leading to protein synthesis. Akt also phosphorylates and inhibits FoxOs, which is a negative regulator of myogenesis. Myostatin/activin signaling: Myostatin/activin binds to type II receptor (ActRIIB) and induces its dimerization with the activin type I receptor. Subsequent phosphorylation of Smad2/3 recruits Smad4. The Smad complex is translocated into the nucleus to induce transcriptional changes, which result in muscle wasting. Simultaneously, myostatin/activin reduces Akt activity and suppresses FoxOs phosphorylation. Dephosphorylated FoxOs are translocated into the nucleus and induce the transcription of target genes which regulate the ubiquitin–proteasome and autophagy–lysosome systems. IL-6 signaling: The binding of IL-6 to its receptors induces homodimerization of gp130 and its complex, which activate JAK–STAT-3 signaling. Phosphorylated STAT3 forms a dimer and translocates into the nucleus, leading to increased protein degradation. TNF-a and IL-1 signaling: Binding of TNF-a or IL-1 to its receptor activates the IKK complex which phosphorylates IκBa proteins. This signal-induced phosphorylation targets IκBa for poly-ubiquitination and subsequent degradation by the proteasome, thereby allowing the RelB/p52 complex to translocate to the nucleus to transcribe respective target genes.