Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival.
Muscle wasting and cachexia have long been postulated to be key determinants of cancer-related death, but there has been no direct experimental evidence to substantiate this hypothesis. Here, we show that in several cancer cachexia models, pharmacological blockade of ActRIIB pathway not only prevents further muscle wasting but also completely reverses prior loss of skeletal muscle and cancer-induced cardiac atrophy. This treatment dramatically prolongs survival, even of animals in which tumor growth is not inhibited and fat loss and production of proinflammatory cytokines are not reduced. ActRIIB pathway blockade abolished the activation of the ubiquitin-proteasome system and the induction of atrophy-specific ubiquitin ligases in muscles and also markedly stimulated muscle stem cell growth. These findings establish a crucial link between activation of the ActRIIB pathway and the development of cancer cachexia. Thus ActRIIB antagonism is a promising new approach for treating cancer cachexia, whose inhibition per se prolongs survival.
Zhou
Xiaolan
X
Departments of Metabolic Disorders and Protein Science, Amgen Research, Thousand Oaks, CA 91320, USA.
Wang
Jin Lin
JL
Lu
John
J
Song
Yanping
Y
Kwak
Keith S
KS
Jiao
Qingsheng
Q
Rosenfeld
Robert
R
Chen
Qing
Q
Boone
Thomas
T
Simonet
W Scott
WS
Lacey
David L
DL
Goldberg
Alfred L
AL
Han
H Q
HQ
D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors* / Q000235:genetics; D028341:Activins / Q000378:metabolism; D000818:Animals; D000855:Anorexia / Q000188:drug therapy / Q000209:etiology; D001284:Atrophy / Q000188:drug therapy / Q000209:etiology; D002100:Cachexia / Q000188:drug therapy* / Q000209:etiology; D005260:Female; D006801:Humans; D007265:Inhibins / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000473:pathology; D009133:Muscular Atrophy / Q000188:drug therapy* / Q000209:etiology; D032446:Myoblasts / Q000473:pathology; D009206:Myocardium / Q000473:pathology*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000150:complications* / Q000401:mortality; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D053583:Interleukin-1beta; D015850:Interleukin-6; D009124:Muscle Proteins; D014409:Tumor Necrosis Factor-alpha; D028341:Activins; D007265:Inhibins; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B