Dystrophin glycoprotein complex dysfunction: a regulatory link between muscular dystrophy and cancer cachexia.
Cachexia contributes to nearly a third of all cancer deaths, yet the mechanisms underlying skeletal muscle wasting in this syndrome remain poorly defined. We report that tumor-induced alterations in the muscular dystrophy-associated dystrophin glycoprotein complex (DGC) represent a key early event in cachexia. Muscles from tumor-bearing mice exhibited membrane abnormalities accompanied by reduced levels of dystrophin and increased glycosylation on DGC proteins. Wasting was accentuated in tumor mdx mice lacking a DGC but spared in dystrophin transgenic mice that blocked induction of muscle E3 ubiquitin ligases. Furthermore, DGC deregulation correlated positively with cachexia in patients with gastrointestinal cancers. Based on these results, we propose that, similar to muscular dystrophy, DGC dysfunction plays a critical role in cancer-induced wasting.
Acharyya
Swarnali
S
Human Cancer Genetics Program, The Ohio State University, Columbus, Ohio 43210, USA.
Butchbach
Matthew E R
ME
Sahenk
Zarife
Z
Wang
Huating
H
Saji
Motoyasu
M
Carathers
Micheal
M
Ringel
Matthew D
MD
Skipworth
Richard J E
RJ
Fearon
Kenneth C H
KC
Hollingsworth
Michael A
MA
Muscarella
Peter
P
Burghes
Arthur H M
AH
Rafael-Fortney
Jill A
JA
Guttridge
Denis C
DC
D000328:Adult; D000368:Aged; D000818:Animals; D002100:Cachexia / Q000150:complications / Q000378:metabolism*; D016189:Dystrophin / Q000378:metabolism / Q000502:physiology*; D049029:Dystrophin-Associated Proteins / Q000378:metabolism / Q000502:physiology*; D005260:Female; D018703:Founder Effect; D006023:Glycoproteins / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D016189:Dystrophin; D049029:Dystrophin-Associated Proteins; D006023:Glycoproteins; D044767:Ubiquitin-Protein Ligases