Seminal Plasma Proteins as Androgen Receptor Corregulators Promote Prostate Cancer Growth
Technical Report,23 Sep 2013,22 Sep 2016
Johns Hopkins University Baltimore United States
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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 andor 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 M zinc and significant stimulatory effects at 100 M zinc on androgen-enhanced AR transactivation. Using co-immunoprecipitation, 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 NC-terminus interactions. More importantly, the LxxLL motif Lleucine xany amino acids present in SgI is likely to be essential and sufficient for mediating the interaction with AR. We further showed in vitro data suggesting that SgI peptides containing the LxxLL motif could prevent the function of SgI in the presence of zinc as well as in vivo data suggesting that SgI might correlate with induction of tumorigenesis.
- Medicine and Medical Research