title: Semenogelin I promotes prostate cancer cell growth via functioning as an androgen receptor coactivator and protecting against zinc cytotoxicity.
abstract: A seminal plasma protein, semenogelin I (SgI), contributes to sperm clotting, upon binding to Zn(2+), and can be proteolyzed by prostate-specific antigen (PSA), resulting in release of the trapped spermatozoa after ejaculation. In contrast, the role of SgI in the development and progression of any types of malignancies remains largely unknown. We previously demonstrated that SgI was overexpressed in prostate cancer tissues and its expression was enhanced by zinc treatment in LNCaP cells. In the current study, using cell lines stably expressing SgI, we investigated its biological functions, in conjunction with zinc, androgen, and androgen receptor (AR), in prostate cancer. Zinc, without SgI, inhibited cell growth of both AR-positive and AR-negative lines. Co-expression of SgI prevented zinc inhibiting dihydrotestosterone-mediated proliferation of AR-positive cells, whereas SgI and/or dihydrotestosterone showed marginal effects in AR-negative cells. Similar effects of SgI overexpression in LNCaP on dihydrotestosterone-induced cell invasion, such as its significant enhancement with zinc, were seen. Overexpression of SgI in LNCaP and CWR22Rv1 cells also augmented dihydrotestosterone-mediated PSA expression (mRNA, protein) in the presence of zinc. However, culture in the conditioned medium containing secreted forms of SgI failed to significantly increase cell viability with or without zinc. In luciferase reporter gene assays, SgI showed even slight inhibitory effects (8% and 15% decreases in PC3 and CWR22Rv1, respectively) at 0 μM zinc and significant stimulatory effects (2.1- and 3.2-fold) at 100 μM zinc on dihydrotestosterone-enhanced AR transactivation. Co-immunoprecipitation then demonstrated dihydrotestosterone-induced physical interactions between AR and SgI. These results suggest that intracellular SgI, together with zinc, functions as an AR coactivator and thereby promotes androgen-mediated prostate cancer progression.
authors.affiliation: Department of Pathology and Urology, Johns Hopkins University School of Medicine Baltimore, MD, USA ; Department of Pathology and Laboratory Medicine, University of Rochester Medical Center Rochester, NY, USA.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ishiguro
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center Rochester, NY, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Izumi
authors.affiliation: Department of Pathology and Urology, Johns Hopkins University School of Medicine Baltimore, MD, USA.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kashiwagi
authors.affiliation: Department of Pathology and Urology, Johns Hopkins University School of Medicine Baltimore, MD, USA ; Department of Pathology and Laboratory Medicine, University of Rochester Medical Center Rochester, NY, USA ; Department of Urology, 2nd Affiliated Hospital, Zhejiang University School of Medicine Hangzhou, China.
authors.forename: Yichun
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center Rochester, NY, USA ; Department of Urology, 2nd Affiliated Hospital, Zhejiang University School of Medicine Hangzhou, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology and Urology, Johns Hopkins University School of Medicine Baltimore, MD, USA ; Department of Pathology and Laboratory Medicine, University of Rochester Medical Center Rochester, NY, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawahara
authors.affiliation: Department of Pathology and Urology, Johns Hopkins University School of Medicine Baltimore, MD, USA ; Department of Pathology and Laboratory Medicine, University of Rochester Medical Center Rochester, NY, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyamoto
keywords: Androgen receptor; prostate cancer; prostate-specific antigen; semenogelin; zinc