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      STAT3 Activation in Skeletal Muscle Links Muscle Wasting and the Acute Phase Response in Cancer Cachexia

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          Abstract

          Background

          Cachexia, or weight loss despite adequate nutrition, significantly impairs quality of life and response to therapy in cancer patients. In cancer patients, skeletal muscle wasting, weight loss and mortality are all positively associated with increased serum cytokines, particularly Interleukin-6 (IL-6), and the presence of the acute phase response. Acute phase proteins, including fibrinogen and serum amyloid A (SAA) are synthesized by hepatocytes in response to IL-6 as part of the innate immune response. To gain insight into the relationships among these observations, we studied mice with moderate and severe Colon-26 (C26)-carcinoma cachexia.

          Methodology/Principal Findings

          Moderate and severe C26 cachexia was associated with high serum IL-6 and IL-6 family cytokines and highly similar patterns of skeletal muscle gene expression. The top canonical pathways up-regulated in both were the complement/coagulation cascade, proteasome, MAPK signaling, and the IL-6 and STAT3 pathways. Cachexia was associated with increased muscle pY705-STAT3 and increased STAT3 localization in myonuclei. STAT3 target genes, including SOCS3 mRNA and acute phase response proteins, were highly induced in cachectic muscle. IL-6 treatment and STAT3 activation both also induced fibrinogen in cultured C2C12 myotubes. Quantitation of muscle versus liver fibrinogen and SAA protein levels indicates that muscle contributes a large fraction of serum acute phase proteins in cancer.

          Conclusions/Significance

          These results suggest that the STAT3 transcriptome is a major mechanism for wasting in cancer. Through IL-6/STAT3 activation, skeletal muscle is induced to synthesize acute phase proteins, thus establishing a molecular link between the observations of high IL-6, increased acute phase response proteins and muscle wasting in cancer. These results suggest a mechanism by which STAT3 might causally influence muscle wasting by altering the profile of genes expressed and translated in muscle such that amino acids liberated by increased proteolysis in cachexia are synthesized into acute phase proteins and exported into the blood.

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          Most cited references67

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          Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins.

          Through the study of transcriptional activation in response to interferon alpha (IFN-alpha) and interferon gamma (IFN-gamma), a previously unrecognized direct signal transduction pathway to the nucleus has been uncovered: IFN-receptor interaction at the cell surface leads to the activation of kinases of the Jak family that then phosphorylate substrate proteins called STATs (signal transducers and activators of transcription). The phosphorylated STAT proteins move to the nucleus, bind specific DNA elements, and direct transcription. Recognition of the molecules involved in the IFN-alpha and IFN-gamma pathway has led to discoveries that a number of STAT family members exist and that other polypeptide ligands also use the Jak-STAT molecules in signal transduction.
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            Stat3 as an oncogene.

            STATs are latent transcription factors that mediate cytokine- and growth factor-directed transcription. In many human cancers and transformed cell lines, Stat3 is persistently activated, and in cell culture, active Stat3 is either required for transformation, enhances transformation, or blocks apoptosis. We report that substitution of two cysteine residues within the C-terminal loop of the SH2 domain of Stat3 produces a molecule that dimerizes spontaneously, binds to DNA, and activates transcription. The Stat3-C molecule in immortalized fibroblasts causes cellular transformation scored by colony formation in soft agar and tumor formation in nude mice. Thus, the activated Stat3 molecule by itself can mediate cellular transformation and the experiments focus attention on the importance of constitutive Stat3 activation in human tumors.
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              IKKbeta/NF-kappaB activation causes severe muscle wasting in mice.

              Muscle wasting accompanies aging and pathological conditions ranging from cancer, cachexia, and diabetes to denervation and immobilization. We show that activation of NF-kappaB, through muscle-specific transgenic expression of activated IkappaB kinase beta (MIKK), causes profound muscle wasting that resembles clinical cachexia. In contrast, no overt phenotype was seen upon muscle-specific inhibition of NF-kappaB through expression of IkappaBalpha superrepressor (MISR). Muscle loss was due to accelerated protein breakdown through ubiquitin-dependent proteolysis. Expression of the E3 ligase MuRF1, a mediator of muscle atrophy, was increased in MIKK mice. Pharmacological or genetic inhibition of the IKKbeta/NF-kappaB/MuRF1 pathway reversed muscle atrophy. Denervation- and tumor-induced muscle loss were substantially reduced and survival rates improved by NF-kappaB inhibition in MISR mice, consistent with a critical role for NF-kappaB in the pathology of muscle wasting and establishing it as an important clinical target for the treatment of muscle atrophy.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                20 July 2011
                : 6
                : 7
                : e22538
                Affiliations
                [1 ]Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America
                [2 ]Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, Florida, United States of America
                [3 ]Center for Computational Science, University of Miami Miller School of Medicine, Miami, Florida, United States of America
                [4 ]Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University School of Medicine, Columbus, Ohio, United States of America
                [5 ]Division of Surgical Oncology, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, United States of America
                [6 ]Division of Burns, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, United States of America
                McMaster University, Canada
                Author notes

                Conceived and designed the experiments: AB TA LGK TAZ. Performed the experiments: AB TA NK LGK TAZ. Analyzed the data: AB TA NK LGK TAZ. Contributed reagents/materials/analysis tools: DCG SK. Wrote the paper: AB TA TAZ.

                [¤]

                Current address: Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America

                Article
                10-PONE-RA-18641
                10.1371/journal.pone.0022538
                3140523
                21799891
                0ee265e3-1dbf-417f-b109-e8d3e6e2e015
                Bonetto et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 6 May 2010
                : 29 June 2011
                Page count
                Pages: 17
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Musculoskeletal System
                Muscle
                Muscle Biochemistry
                Biochemistry
                Proteins
                Acute Phase Proteins
                Immunology
                Immunity
                Inflammation
                Immune Response
                Medicine
                Anatomy and Physiology
                Musculoskeletal System
                Muscle
                Muscle Biochemistry
                Oncology
                Basic Cancer Research
                Tumor Physiology

                Uncategorized
                Uncategorized

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