Cancer cachexia is regulated by selective targeting of skeletal muscle gene products.
Cachexia is a syndrome characterized by wasting of skeletal muscle and contributes to nearly one-third of all cancer deaths. Cytokines and tumor factors mediate wasting by suppressing muscle gene products, but exactly which products are targeted by these cachectic factors is not well understood. Because of their functional relevance to muscle architecture, such targets are presumed to represent myofibrillar proteins, but whether these proteins are regulated in a general or a selective manner is also unclear. Here we demonstrate, using in vitro and in vivo models of muscle wasting, that cachectic factors are remarkably selective in targeting myosin heavy chain. In myotubes and mouse muscles, TNF-alpha plus IFN-gamma strongly reduced myosin expression through an RNA-dependent mechanism. Likewise, colon-26 tumors in mice caused the selective reduction of this myofibrillar protein, and this reduction correlated with wasting. Under these conditions, however, loss of myosin was associated with the ubiquitin-dependent proteasome pathway, which suggests that mechanisms used to regulate the expression of muscle proteins may be cachectic factor specific. These results shed new light on cancer cachexia by revealing that wasting does not result from a general downregulation of muscle proteins but rather is highly selective as to which proteins are targeted during the wasting state.
Division of Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus 43210, USA.
Swarnali
S
Acharyya
Katherine J
KJ
Ladner
Lori L
LL
Nelsen
Jeffrey
J
Damrauer
Peter J
PJ
Reiser
Steven
S
Swoap
Denis C
DC
Guttridge
D000818:Animals; D016466:CHO Cells; D002100:Cachexia / Q000378:metabolism*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000150:complications* / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D018390:Gene Targeting; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009097:Multienzyme Complexes / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D017570:MyoD Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D012680:Sensitivity and Specificity; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D014452:Ubiquitins / Q000378:metabolism
D009097:Multienzyme Complexes; D017570:MyoD Protein; D014409:Tumor Necrosis Factor-alpha; D014452:Ubiquitins; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D018995:Myosin Heavy Chains