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Activin ß_C-Subunit Heterodimers Provide a New Mechanism of Regulating Activin Levels in the Prostate

Monash Institute of Reproduction and Development, Monash University (S.L.M., E.M.A.B., A.E.O., J.F.S., D.J.P., G.P.R.), Melbourne, Victoria 3168, Australia; Prince Henry’s Institute of Medical Research (J.-F.E.), Clayton, Victoria 3168, Australia; and School of Biological and Molecular Sciences, Oxford Brookes University (M.C., N.P.G.), Headington 0X3 0BP, Oxford, United Kingdom

Address all correspondence and requests for reprints to: Prof. Gail P. Risbridger, Centre for Urological Research, Monash Institute of Reproduction and Development, Monash Medical Center, 246 Clayton Road, Clayton, Victoria 3168, Australia. E-mail: gail.risbridger{at}med.monash.edu.au.

Activins are formed by dimerization of ß-subunits and, as members of the TGF-ß superfamily, have diverse roles as potent growth and differentiation factors. As the biological function of the activin C homodimer (ß_C-ß_C) is unknown, we sought to compare activin A (ß_A-ß_A), B (ß_B-ß_B), and C homodimer bioactivities and to investigate the consequences of activin ß_C-subunit overexpression in prostate tumor cells. Exogenous activin A and B homodimers inhibited cell growth and activated activin-responsive promoters. In contrast, the activin C homodimer was unable to elicit these responses. We previously showed that the activin ß_C-subunit heterodimerized with activin ß_A in vitro to form activin AC. Therefore, we hypothesize that the activin ß_C-subunit regulates the levels of bioactive activin A by the formation of activin AC heterodimers. To test this hypothesis, we measured activin AC heterodimer production using a novel specific two-site ELISA that we developed for this purpose. In the PC3 human prostate tumor cell line, activin ß_C-subunit overexpression increased activin AC heterodimer levels, concomitantly reduced activin A levels, and decreased activin signaling. Overall, these data are consistent with a role for the activin ß_C-subunit as a regulatory mechanism to reduce activin A secretion via intracellular heterodimerization.

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