Regulation of Bcl-2 Expression by Dihydrotestosterone in Hormone Sensitive LNCaP-FGC Prostate Cancer Cells

Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas, United States
The Journal of Urology (Impact Factor: 4.47). 05/2003; 169(4):1553-7. DOI: 10.1097/01.ju.0000055140.91204.c7
Source: PubMed


Up-regulation of the anti-apoptotic bcl-2 proto-oncogene is associated with androgen independent prostate cancer progression. This observation suggests that the expression of bcl-2 may be negatively regulated by androgens in prostate cancer cells.
The expression of the proto-oncogene bcl-2 was assessed in the hormone sensitive prostate cancer cell line LNCaP-FGC in the presence and absence of a physiological concentration of 1 nM. dihydrotestosterone (DHT). Sequence analysis of the bcl-2 promoter regions demonstrated the presence of 2 potential androgen response elements. Transient transfections of luciferase reporter constructs containing these potential androgen response elements into LNCaP-FGC cells in the presence and absence of DHT were performed. Steady-state transcripts of bcl-2 were assessed using RNase protection assays.
Cells cultured in charcoal stripped serum in the presence of DHT resulted in down-regulation of bcl-2 protein. Down-regulation of bcl-2 protein and mRNA by DHT was inhibited by coincubation with the antiandrogen bicalutamide, an agent that competitively inhibits binding of DHT to androgen receptor. Luciferase reporter constructs containing candidate androgen response elements were transrepressed in the presence of DHT. Bcl-2 mRNA was also down-regulated by DHT and this down-regulation could not be abolished by cycloheximide.
Together these results suggest that the suppression of bcl-2 expression by DHT in hormone sensitive LNCaP-FGC prostate cancer cells occurs directly. In addition, these results provide a possible mechanistic basis for the up-regulation (derepression) of bcl-2 observed in hormone independent prostate cancers.

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    • "Mature prostate epithelial cells are non-proliferative cells which are highly sensitive to apoptotic stimuli. (Due to the specific regulation of the expression of genes belonging to the Bcl-2 family, anti-apoptotic Bcl-2 gene expression is repressed whereas pro-apoptotic Bax gene expression is stimulated by androgen receptors [42] [43] [44]). "
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    ABSTRACT: The progression of cells from a normal differentiated state in which rates of proliferation and apoptosis are balanced to a tumorigenic and metastatic state involves the accumulation of mutations in multiple key signalling proteins and the evolution and clonal selection of more aggressive cell phenotypes. These events are associated with changes in the expression of numerous other proteins. This process of tumorigenesis involves the altered expression of one or more TRP proteins, depending on the nature of the cancer. The most clearly described changes are those involving TRPM8, TRPV6 and TRPM1. Expression of TRPM8 is substantially increased in androgen-dependent prostate cancer cells, but is decreased in androgen independent and metastatic prostate cancer. TRPM8 expression is regulated, in part, by androgens, most likely through androgen response elements in the TRPM8 promoter region. TRPM8 channels are involved in the regulation of cell proliferation and apoptosis. Expression of TRPV6 is also increased in prostate cancer and in a number of other cancers. In contrast to TRPM8, expression of TRPV6 is not directly regulated by androgens. TRPM1 is highly expressed in early stage melanomas but its expression declines with increases in the degree of aggressiveness of the melanoma. The expression of TRPV1, TRPC1, TRPC6, TRPM4, and TRPM5 is also increased in some cancers. The level of expression of TRPM8 and TRPV6 in prostate cancer, and of TRPM1 in melanomas, potentially provides a good prognostic marker for predicting the course of the cancer in individuals. The Drosophila melanogaster, TRPL, and the TRPV1 and TRPM8 proteins, have been used to try to develop strategies to selectively kill cancer cells by activating Ca(2+) and Na(+) entry, producing a sustained increase in the cytoplasmic concentration of these ions, and subsequent cell death by apoptosis and necrosis. TRPV1 is expressed in neurones involved in sensing cancer pain, and is a potential target for pharmacological inhibition of cancer pain in bone metastases, pancreatic cancer and most likely in other cancers. Further studies are required to assess which other TRP proteins are associated with the development and progression of cancer, what roles TRP proteins play in this process, and to develop further knowledge of TRP proteins as targets for pharmaceutical intervention and targeting in cancer.
    Preview · Article · Sep 2007 · Biochimica et Biophysica Acta
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    • "5α-dihydrotestosterone (DHT) downregulated bcl-2 in the PC cell line LNCaP-FGC [27] and in the BC cell line ZR-75-1 [28]. This downregulation disappeared when an antagonist of iAR was added. "
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    ABSTRACT: The Estradiol-Dihydrotestosterone model of prostate cancer (PC) showed how the interaction of hormones with specific hormone receptors affected apoptosis. The same hormone can produce different effects, depending on which hormone receptor it interacts with. This model proposes that the first step in the development of most PC and breast cancer (BC) occurs when aromatase converts testosterone to estradiol (E2). A sufficiently high enough local level of E2 results in telomerase activity. The telomerase activity allows cell division and may lead to BC or PC, which will proliferate if the rate of cell division is greater than the rate of cell death. The effect of hormones on their hormone receptors will affect the rate of cell death and determine whether or not the cancer proliferates. By minimizing bcl-2 and maximizing apoptotic proteins, new systemic treatments for BC and PC can be developed that may be more effective than existing treatments.
    Full-text · Article · Feb 2007 · Theoretical Biology and Medical Modelling
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    • "T-BSA was shown not to bind to iAR. DHT has been shown[19] to decrease bcl-2 production when it binds to the iAR of LNCaP-FGC. This decrease was inhibited by the addition of bicalutamide, an antiandrogen which interferes with the binding of DHT to iAR. "
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    ABSTRACT: Background The exact relationship between hormonal activity and prostate cancer(PCa) has not yet been clearly defined. One of the key hormones associated with PCa is testosterone(T). However, both in vitro and in vivo studies have shown that under some conditions T is capable of either promoting PCa growth or death. This article proposes a theory which resolves this apparent paradox. Model The Estradiol-Dihydrotestosterone(E-D) model introduced in this paper proposes that 17β-estradiol(E2) is essential for initiating the growth of PCa cells through the formation of telomeres. It also proposes that T is responsible for increasing the expression of proteins which cause apoptosis, or programmed cell death, and that 5α-dihydrotestosterone(DHT) is essential for preventing this. In addition, it is known that some T is converted to both E2 and DHT, which means that depending on the conditions, T is capable of either promoting the growth of or the killing of PCa.
    Full-text · Article · Apr 2005 · Theoretical Biology and Medical Modelling
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