title: Systemic inflammation correlates with increased expression of skeletal muscle ubiquitin but not uncoupling proteins in cancer cachexia.
abstract: Muscle wasting in experimental cancer cachexia has been associated with increased ubiquitin proteasome proteolytic system activity and increased uncoupling protein (UCP) expression. Increased ubiquitin proteasome pathway activity has also been found in gastric, but not lung, cancer patients. It therefore remains unclear in which patients modulation of this proteolytic system could be a therapeutic target. We investigated markers of systemic inflammation, hypermetabolism and expression of ubiquitin and uncoupling proteins 2 and 3 in muscle of pancreatic cancer patients. Rectus abdominis muscle was sampled from 15 weight-losing pancreatic cancer patients and 11 controls. UCP2 and 3, and ubiquitin mRNA expression were measured by Northern blots and UCP3 protein by Western blotting. Resting energy expenditure and plasma IL-6, sTNF-R and C-reactive protein (CRP) were also measured. Cancer patients had lost 18% of pre-illness stable weight, but were not significantly hypermetabolic compared with controls. IL-6, sTNF-R and CRP levels and ubiquitin 2.4 kb, but not 1.2 kb, mRNA expression were increased in cancer patients. UCP-2 and 3 mRNA and UCP-3 protein were similar in both groups. Weight loss correlated with systemic inflammation and ubiquitin 1.2 and 2.4 kb mRNA expression. Weight loss in pancreatic cancer is associated with systemic inflammation and increased mRNA expression for ubiquitin but not uncoupling proteins in skeletal muscle. The pro-inflammatory network and ubiquitin proteasome pathway may be targets for intervention in pancreatic cancer cachexia.
authors.affiliation: Department of Surgery, University Hospital Maastricht, PO Box 5800, Maastricht NL-6202 AZ, The Netherlands. c.dejong@surgery.azm.nl
authors.forename: Cornelis H C
authors.initials: CH
authors.lastname: DeJong
authors.forename: Sylvia
authors.initials: S
authors.lastname: Busquets
authors.forename: Alastair G W
authors.initials: AG
authors.lastname: Moses
authors.forename: Patrick
authors.initials: P
authors.lastname: Schrauwen
authors.forename: Jim A
authors.initials: JA
authors.lastname: Ross
authors.forename: Josep M
authors.initials: JM
authors.lastname: Argiles
authors.forename: Kenneth C H
authors.initials: KC
authors.lastname: Fearon
mesh_terms: D000368:Aged; D015152:Blotting, Northern; D015153:Blotting, Western; D001827:Body Height; D001835:Body Weight; D002097:C-Reactive Protein / Q000378:metabolism; D002100:Cachexia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D004734:Energy Metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015850:Interleukin-6 / Q000097:blood; D007473:Ion Channels; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood; D015398:Signal Transduction; D012995:Solubility; D013223:Statistics as Topic; D025801:Ubiquitin / Q000235:genetics*; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3
chemical_list: D002352:Carrier Proteins; D015850:Interleukin-6; D007473:Ion Channels; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; C000604389:UCP2 protein, human; C000604392:UCP3 protein, human; D025801:Ubiquitin; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D002097:C-Reactive Protein; D046988:Proteasome Endopeptidase Complex