Acquisition of androgen independence by human prostate epithelial cells during arsenic-induced malignant transformation.
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.
Benbrahim-Tallaa
Lamia
L
Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at the National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Webber
Mukta M
MM
Waalkes
Michael P
MP
D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000378:metabolism; D013196:Dihydrotestosterone / Q000494:pharmacology; D004815:Epidermal Growth Factor; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D005485:Flutamide / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D010902:Pituitary Gland / Q000737:chemistry; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism
D000726:Androgen Antagonists; D000728:Androgens; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D012333:RNA, Messenger; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D004958:Estradiol; D004815:Epidermal Growth Factor; D005485:Flutamide; D001151:Arsenic