Abstract
BackgroundProgressive loss of skeletal muscle, termed muscle wasting, is a hallmark of cancer cachexia and contributes to weakness, reduced quality of life, as well as poor response to therapy. Previous studies have indicated that systemic host inflammatory response regarding tumor development results in muscle wasting. However, how tumor directly regulates muscle wasting via tumor-derived secreted proteins is still largely unknown.MethodsIn this study, we performed bioinformatics analysis in two datasets of pancreatic ductal adenocarcinoma, which causes cancer cachexia and muscle wasting with the highest prevalence, and uncovered that IGFBP3, which encodes IGF-binding protein-3 (IGFBP-3), is dramatically up-regulated in pancreatic tumor samples. We also verified the wasting effect of IGFBP-3 on C2C12 muscle cells with biochemical and genetic assays.ResultsIGFBP-3 potently leads to impaired myogenesis and enhanced muscle protein degradation, the major features of muscle wasting, via IGF signaling inhibition. Moreover, conditioned medium from Capan-1 pancreatic cancer cells, which contains abundant IGFBP-3, significantly induces muscle cell wasting. This wasting effect is potently alleviated by IGFBP3 knockdown in Capan-1 cells or IGFBP-3 antibody neutralization. Strikingly, compared to muscle cells, IGF signaling and proliferation rate of Capan-1 cells were rarely affected by IGFBP-3 treatment.ConclusionsOur results demonstrated that pancreatic cancer cells induce muscle wasting via IGFBP-3 production.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0317-z) contains supplementary material, which is available to authorized users.
Highlights
Progressive loss of skeletal muscle, termed muscle wasting, is a hallmark of cancer cachexia and contributes to weakness, reduced quality of life, as well as poor response to therapy
We further demonstrated that insulin-like growth factors (IGFs)-binding protein-3 (IGFBP-3), which is abundantly produced in pancreatic cancer cells, causes muscle wasting through both impaired myogenesis and enhanced myotube protein degradation via, at least, inhibition of IGF/PI3K/AKT signaling
Our results indicated that insulin-like growth factor binding protein (IGFBP)-3 impairs C2C12 myogenesis and promotes C2C12 myotube wasting via suppression of IGF-1/PI3K/AKT signaling
Summary
Progressive loss of skeletal muscle, termed muscle wasting, is a hallmark of cancer cachexia and contributes to weakness, reduced quality of life, as well as poor response to therapy. Previous studies have indicated that systemic host inflammatory response regarding tumor development results in muscle wasting. Previous studies have indicated that the progressive loss of skeletal muscle, termed muscle wasting, is a key phenotype of cancer cachexia and results in weakness, reduced ambulation, diminished quality of life, poor response to therapy, as well as death due to respiratory failure or infection [3]. Systemic inflammatory cytokines, including TNFα, IL-1α, IL-1β, IL-6 and related ligands haven been shown to cause muscle wasting in both mouse models and human samples [9]. Conditioned medium from pancreatic cancer cells that contains numerous cancer-derived peptides, including Myostatin and activin A, is sufficient to cause
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