The actions of Activin C and its mechanism towards the progression of Prostate disease

Abstract

The Transforming Growth Factor β (TGF β) superfamily is involved with regulating many biological and physiological processes. Activins are members of the TGF β superfamily. Four activin subunits (βA, βB, βC and βE) have been characterized in mammalian cells. Activin A is a negative growth regulator in the prostate and dysregulation is associated with prostate disease. Activin βC was discovered only in the last decade. Recently it was shown that activin βC regulated the expression and bioactivity of activin A, and over-expression led to the development of prostate disease in mice aged 3 months. The current study hypothesized that activin βC functions locally to antagonize the activity of activin A, and over expression of activin βC can therefore lead to the formation of overt prostate disease in aged mice.

We used overexpressing activin βC transgenic mice (TG) aged 12 months, and studied the dorsal and ventral prostate. There were clear signs of hyperplasia in the TG prostate epithelial cells, and some abnormally stained nuclei indicative of mucinous metaplasia. The prostate weights had also increased due to a significant increase in epithelial cells. Immunohistochemistry was then performed for PCNA and the results indicated no increase in cellular proliferation. However, a decrease in apoptosis was also evident as was a decrease in p-SMAD 2 signaling in the dorsal prostate. Thus supporting our hypothesis that increased activin βC antagonized the growth inhibitory effects of activin A and this was the mechanism underlying the alterations in proliferation and apoptosis.

Pathway focused gene expression was then undertaken in the dorsal prostate to assess the mechanism by which over-expression of activin βC decreased proliferation, apoptosis, and SMAD 2 signaling. An increase in gene expression of activin βA and βB, the activin receptors, as well as the SMAD signaling molecules were evident. In addition, an increase expression of gene in the negative regulation of cell cycle was observed in TG samples, indicating that these cells were signaled for growth arrest. This validates the decreased PCNA and apoptosis data in the TG prostate sections.

Finally, correlation with human prostate pathology was determined by assessing the staining of activin βA and activin βC in human prostate disease arrays. Activin βA was increased in all prostate disease whereas activin βC was only increased in benign prostatic hyperplasia. Therefore we conclude that activin C is associated with benign disease and not prostate cancer in mice and men.