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

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...

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Vydané v:	PloS one Ročník 6; číslo 7; s. e22538
Hlavní autori:	Bonetto, Andrea, Aydogdu, Tufan, Kunzevitzky, Noelia, Guttridge, Denis C., Khuri, Sawsan, Koniaris, Leonidas G., Zimmers, Teresa A.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Public Library of Science 20.07.2011 Public Library of Science (PLoS)
Predmet:	Activation Acute phase proteins Acute phase substances Acute-Phase Reaction - blood Acute-Phase Reaction - etiology Acute-Phase Reaction - genetics Acute-Phase Reaction - metabolism Amino acids Amyloid Anatomy & physiology Animals Apoptosis Biology Burns Cachexia Cachexia - blood Cachexia - complications Cachexia - genetics Cachexia - metabolism Cancer Cancer treatment Cell Line, Tumor Chemical synthesis Coagulation Colon Colonic Neoplasms - complications Cytokines Cytokines - blood Female Fibrin Fibrinogen Gene expression Gene Expression Regulation, Neoplastic Genes Hepatocytes Humans Illnesses Immune response Immune system Innate immunity Insulin Interleukin 6 Interleukins Kinases Liver Liver - metabolism Liver - pathology Localization MAP kinase Medicine Metabolism Mice Mortality Muscle, Skeletal - growth & development Muscle, Skeletal - metabolism Muscle, Skeletal - pathology Musculoskeletal system Myotubes Nutrition Patients Physiology Proteasomes Proteins Proteolysis Quality of life Quantitation RNA Rodents Signaling Skeletal muscle Stat3 protein STAT3 Transcription Factor - metabolism Surgery Transcriptome Tumor necrosis factor-TNF Tumors Weight control Weight loss Florida United States > US
ISSN:	1932-6203, 1932-6203
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Shrnutí:	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. 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. 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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Current address: Sanford-Burnham Medical Research Institute, La Jolla, California, United States of America 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.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0022538