| Acquisition of Androgen Independence by Human Prostate Epithelial Cells during Arsenic-Induced Malignant Transformation Lamia Benbrahim-Tallaa,1 Mukta M. Webber,2,3 and
Michael P. Waalkes1 1Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis,
National Cancer Institute at the National Institute of Environmental Health
Sciences, National Institutes of Health, Department of Health and Human Services,
Research Triangle Park, North Carolina, USA; 2Department of Medicine,
and 3Department of Zoology, Michigan State University, East Lansing,
Michigan, USA Abstract
Lethal phenotypes of human prostate cancer are characterized by progression to androgen independence, although the mechanisms behind this progression remain unclear. Arsenic is a potential human prostate carcinogen that may affect tumor progression. In this study, we used a prostate cancer cell model in which an immortalized, nontumorigenic human prostate epithelial cell line (RWPE-1) had been malignantly transformed by chronic low-level arsenic to help determine whether arsenic affects prostate tumor progression. Control and CAsE-PE (chronic-arsenic-exposed human prostate epithelial) cells were continuously maintained in a complete medium [keratinocyte serum-free medium (K-SFM) with bovine pituitary extract and epidermal growth factor] or in a steroid-depleted medium (K-SFM alone) . The arsenic-transformed cells showed a more rapid proliferation rate in complete medium than did control cells and also showed sustained proliferation in steroid-reduced medium. Although both control and CAsE-PE cells showed similar levels of androgen receptor (AR) , androgens were less effective in stimulating cell proliferation and AR-related gene expression in CAsE-PE cells. For instance, dihydrotestosterone caused a 4.5-fold increase in prostate-specific antigen transcript in control cells but only a 1.5-fold increase in CAsE-PE cells. CAsE-PE cells also showed relatively low levels of growth stimulation by nonandrogen steroids, such as estradiol. Thus, arsenic-induced malignant transformation is associated with acquired androgen independence in human prostate cells. This acquired androgen independence was apparently not due to AR up-regulation, increased activity, or altered ligand specificity. The precise manner in which arsenic altered CAsE-PE growth and progression is undefined but may involve a bypass of AR involving direct stimulation of downstream signaling pathways. Key words: androgen independent, AR, arsenic, cancer progression, malignant transformation, prostate. Environ Health Perspect 113:1134-1139 (2005) . doi:10.1289/ehp.7832 available via http://dx.doi.org/ [Online 5 May 2005]
Address correspondence to M.P. Waalkes, Inorganic Carcinogenesis Section, NCI at NIEHS, P.O. Box 12233, Mail Drop F0-09, 111 Alexander Dr., Research Triangle Park, NC 27709 USA. Telephone: (919) 541-2328. Fax: (919) 541-3970. E-mail: waalkes@niehs.nih.gov We thank L. Keefer, J. Liu, and W. Qu for their critical review of the manuscript. The authors declare they have no competing financial interests. Received 7 December 2004 ; accepted 5 May 2005.
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