title: Activin-β(c)  reduces reproductive tumour progression and abolishes cancer-associated cachexia in inhibin-deficient mice.
abstract: Activins are involved in the regulation of a diverse range of physiological processes including development, reproduction, and fertility, and have been implicated in the progression of cancers. Bioactivity is regulated by the inhibin α-subunit and by an activin-binding protein, follistatin. The activin-β(C)  subunit was not considered functionally significant in this regard due to an absence of phenotype in knockout mice. However, activin-β(C)  forms heterodimers with activin-β(A)  and activin-C antagonizes activin-A in vitro. Thus, it is proposed that overexpression, rather than loss of activin-β(C) , regulates activin-A bioactivity. In order to prove biological efficacy, inhibin α-subunit knockout mice (α-KO) were crossed with mice overexpressing activin-β(C)  (ActC++). Deletion of inhibin leads to Sertoli and granulosa cell tumours, increased activin-A, and cancer-associated cachexia. Therefore, cachexia and reproductive tumour development should be modulated in α-KO/ActC++ mice, where excessive activin-A is the underlying cause. Accordingly, a reduction in activin-A, no significant weight loss, and reduced incidence of reproductive tumours were evident in α-KO/ActC++ mice. Overexpression of activin-β(C)  antagonized the activin signalling cascade; thus, the tumourigenic effects of activin-A were abrogated. This study provides proof of the biological relevance of activin-β(C) . Being a regulator of activin-A, it is able to abolish cachexia and modulate reproductive tumour development in α-KO mice.
authors.affiliation: Department of Anatomy, University of Otago, Dunedin, New Zealand. Elspeth.Gold@otago.ac.nz
authors.forename: Elspeth
authors.initials: E
authors.lastname: Gold
authors.forename: Francesco Elia
authors.initials: FE
authors.lastname: Marino
authors.forename: Craig
authors.initials: C
authors.lastname: Harrison
authors.forename: Yogeshwar
authors.initials: Y
authors.lastname: Makanji
authors.forename: Gail
authors.initials: G
authors.lastname: Risbridger
mesh_terms: D028341:Activins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002100:Cachexia / Q000235:genetics*; D002460:Cell Line; D049109:Cell Proliferation; D019281:Dimerization; D018450:Disease Progression; D005260:Female; D038681:Follistatin / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D028322:Inhibin-beta Subunits / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D017384:Sequence Deletion; D051899:Smad2 Protein / Q000378:metabolism; D013736:Testicular Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D038681:Follistatin; C497782:SMAD2 protein, human; D051899:Smad2 Protein; C422405:activin A; D028341:Activins; D028322:Inhibin-beta Subunits