Seminal Plasma Proteins as Androgen Receptor Corregulators Promote Prostate Cancer Growth
Abstract
We hypothesized that semenogelins, especially semenogelin I (SgI) in the presence of zinc, promote prostate cancer growth via functioning as androgen receptor (AR) co-activators. Using cell lines stably expressing SgI, we investigated biological functions of SgI in prostate cancer. Zinc, without SgI, inhibited cell growth of both AR-positive and AR-negative lines. Co-expression of SgI prevented zinc inhibiting androgen-mediated proliferation of AR-positive cells, whereas SgI and/or androgen showed marginal effects in AR-negative cells. Culture in the conditioned medium containing secreted forms of SgI failed to significantly increase cell viability with or without zinc. Similar effects of SgI overexpression on androgen-induced cell invasion, such as its significant enhancement with zinc, were seen. Overexpression of SgI also augmented androgen-mediated prostate-specific antigen (mRNA, protein) in the presence of zinc. In luciferase assays, SgI showed even slight inhibitory effects at 0 micro(M) zinc and significant stimulatory effects at 100 micro(M) zinc on androgen-enhanced AR transactivation. Using coimmunoprecipitation, we demonstrated androgen-induced physical interactions between AR and SgI. These results suggest that intracellular SgI, together with zinc, functions as an AR co-activator and thereby promotes androgen-mediated prostate cancer progression. We further found that SgI did not interact with other steroid hormone receptors, including estrogen receptors and glucocorticoid receptor, and did not significantly affect AR N/C-terminus interactions. More importantly, the LxxLL motif (L=leucine; x=any amino acids) present in SgI is likely to be essential and sufficient for mediating the interaction with AR.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2015
- Accession Number
- ADA626126
Entities
People
- Hiroshi Miyamoto
Organizations
- Johns Hopkins University