Abstract
Anorexia-cachexia syndrome (ACS) is a major determinant of cancer-related death that causes progressive body weight loss due to depletion of skeletal muscle mass and body fat. Here, we report the development of a novel preclinical murine model of ACS in which lymphomas harbor elevated Myc and activated mTOR signaling. The ACS phenotype in this model correlated with deregulated expression of a number of cytokines, including elevated levels of interleukin-10 which was under the direct translational control of mTOR. Notably, pharmacologic intervention to impair protein synthesis restored cytokine production to near-normal levels, delayed ACS progression, and extended host survival. Together, our findings suggest a new paradigm to treat ACS by strategies which target protein synthesis to block the production of procachexic factors.
Highlights
Anorexia-cachexia syndrome (ACS) is characterized by loss of adipose tissue and skeletal muscle mass that leads to weight loss exceeding 10% of the patient's preillness weight [1, 2]
Ribosome recruitment is mediated by eukaryotic initiation factor4F, a complex consisting of eIF4E, the cap (m7GpppN; where N is any nucleotide) binding protein; eIF4A, an RNA helicase; and eIF4G, a large scaffolding protein [10]. mTOR regulates translation initiation rates by controlling the availability of eIF4E and eIF4A for assembly into the eIF4F complex [10]
We found that muscle mass and epididymal fat loss occurred concurrently indicating that the reduction in muscle mass was not a secondary consequence due to the absence of adipose tissue (Supplementary Fig. S2)
Summary
Anorexia-cachexia syndrome (ACS) is characterized by loss of adipose tissue and skeletal muscle mass that leads to weight loss exceeding 10% of the patient's preillness weight [1, 2]. One key event downstream of mTOR regulated by this pathway is the ribosome recruitment phase of translation initiation. Ribosome recruitment is mediated by eukaryotic initiation factor (eIF)4F, a complex consisting of eIF4E, the cap (m7GpppN; where N is any nucleotide) binding protein; eIF4A, an RNA helicase; and eIF4G, a large scaffolding protein [10]. MTOR regulates translation initiation rates by controlling the availability of eIF4E and eIF4A for assembly into the eIF4F complex [10]. Loss of the tumor suppressors, PTEN, TSC1, or TSC2, lead to activation of the mTOR kinase and elevated translation initiation rates. We describe a new murine model of ACS consisting of pre-B/B-lymphoma cells overexpressing Myc and exhibiting activated mTOR signaling due to loss of the PTEN, TSC1, or TSC2 tumor suppressor genes. We take advantage of the powerful genetics of this model to develop a new paradigm for treating ACS consisting of targeting protein synthesis to curtail aberrant production of procachexic factors
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