Increase of androgen-induced cell death and androgen receptor transactivation by BRCA1 in prostate cancer cells

Yeh, Shuyuan; Hu, Yueh Chiang; Rahman, Mujib; Lin, Hui Kuan; Hsu, Cheng Lung; Ting, Huei-Ju; Kang, Hong-Yo; Chang, Chawnshang

doi:10.1073/pnas.190353897

Cited by 136 publications

(114 citation statements)

References 51 publications

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“…However, the finding that BRCA1-siRNA stimulates AR activity and partially reverses the inhibition of DHT-induced AR activity by I3C and genistein is somewhat surprising, since wtBRCA1 and wtBRCA2 were reported to stimulate AR signalling (Yeh et al, 2000;Shin and Verma, 2003). Presently, we do not have a good explanation for this discrepancy; but we have observed that wtBRCA1 either has no effect on or modestly enhances DHT-stimulated activation of several AREdriven reporters (ARE-TK-Luc and MMTV-Luc) (unpublished results), suggesting that the consequences of underexpressing BRCA1 may not be predictable based on overexpression models.…”

Section: Discussionmentioning

confidence: 99%

BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells

et al. 2006

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Indole-3-carbinol (I3C) and genistein are naturally occurring chemicals derived from cruciferous vegetables and soy, respectively, with potential cancer prevention activity for hormone-responsive tumours (e.g., breast and prostate cancers). Previously, we showed that I3C induces BRCA1 expression and that both I3C and BRCA1 inhibit oestrogen (E2)-stimulated oestrogen receptor (ER-a) activity in human breast cancer cells. We now report that both I3C and genistein induce the expression of both breast cancer susceptibility genes (BRCA1 and BRCA2) in breast (MCF-7 and T47D) and prostate (DU-145 and LNCaP) cancer cell types, in a time-and dosedependent fashion. Induction of the BRCA genes occurred at low doses of I3C (20 mM) and genistein (0.5 -1.0 mM), suggesting potential relevance to cancer prevention. A combination of I3C and genistein gave greater than expected induction of BRCA expression. Studies using small interfering RNAs (siRNAs) and BRCA expression vectors suggest that the phytochemical induction of BRCA2 is due, in part, to BRCA1. Functional studies suggest that I3C-mediated cytoxicity is, in part, dependent upon BRCA1 and BRCA2. Inhibition of E2-stimulated ER-a activity by I3C and genistein was dependent upon BRCA1; and inhibition of ligand-inducible androgen receptor (AR) activity by I3C and genistein was partially reversed by BRCA1-siRNA. Finally, we provide evidence suggesting that the phytochemical induction of BRCA1 expression is due, in part, to endoplasmic reticulum stress response signalling. These findings suggest that the BRCA genes are molecular targets for some of the activities of I3C and genistein.

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Section: Discussionmentioning

confidence: 99%

BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells

et al. 2006

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“…MG132, lactacystine, and Z-VAD-fmk were purchased from Calbiochem. 5␣-dihydrotestosterone (DHT) was purchased from Sigma, and the anti-AR polyclonal antibody, NH27, was produced as previously described (20,24). The Texas Red-conjugated secondary anti-rabbit antibody was obtained from ICN Pharmaceuticals, Inc.…”

Section: Methodsmentioning

confidence: 99%

“…Some of these coregulators contain E3 ligase activity, which may regulate AR activity via the ubiquitin-proteasome pathway (19,22,24,25). Early evidence suggested that the ubiquitin-proteasome system might be involved in the regulation of AR protein turnover (26).…”

mentioning

confidence: 99%

Proteasome Activity Is Required for Androgen Receptor Transcriptional Activity via Regulation of Androgen Receptor Nuclear Translocation and Interaction with Coregulators in Prostate Cancer Cells

Lin

Altuwaijri

Lin

et al. 2002

Journal of Biological Chemistry

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130

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Upon binding to androgen, the androgen receptor (AR) can translocate into the nucleus and bind to androgen response element(s) to modulate its target genes. Here we have shown that MG132, a 26 S proteasome inhibitor, suppressed AR transactivation in an androgen-dependent manner in prostate cancer LNCaP and PC-3 cells. In contrast, MG132 showed no suppressive effect on glucocorticoid receptor transactivation. Additionally, transfection of PSMA7, a proteasome subunit, enhanced AR transactivation in a dose-dependent manner. The suppression of AR transactivation by MG132 may then result in the suppression of prostate-specific antigen, a well known marker used to monitor the progress of prostate cancer. Further mechanistic studies indicated that MG132 may suppress AR transactivation via inhibition of AR nuclear translocation and/or inhibition of interactions between AR and its coregulators, such as ARA70 or TIF2. Together, our data suggest that the proteasome system plays important roles in the regulation of AR activity in prostate cancer cells and may provide a unique target site for the development of therapeutic drugs to block androgen/AR-mediated prostate tumor growth.The ubiquitin-proteasome system degrades misfolded or unfolded proteins in order to control a variety of biological functions, including cell proliferation, differentiation, and stress response (1-3). The multicomplex 26 S proteasome contains two 19 S regulatory complexes and a 20 S catalytic core complex that may be responsible for 80 -90% of protein degradation in the cell (4). The 19 S complexes are responsible for recognition of the polyubiquitinated protein substrates and work to bridge the substrates to the 20 S core complex for degradation. The barrel-shaped 20 S complex contains four rings, each of which is made up of seven different subunits. The two outer rings contain ␣-type subunits, whereas the inner rings contain ␤-type subunits (4, 5). Several proteins involved in cell cycle regulation, like p27 and cyclin, are known to be degraded by the ubiquitin-proteosome pathway (6 -8). The protein ubiquitination is initiated by multiple enzyme reactions catalyzed by a single ubiquitin-activating enzyme (E1), a few ubiquitin-conjugating enzymes (E2s), 1 and a large variety of ubiquitin-protein ligases (E3s). The intrinsic E3 ligase activity represents the rate limiting step of ubiquitin modification of proteins. Therefore,thecontroloftheE3ligaseactivitymayinfluenceproteasome-dependent protein degradation (2, 5).Proteasomes are known to play an essential role in thymocyte apoptosis and inflammatory responses (9 -12). The proteasome inhibitors, such as MG132, suppress the inflammatory response by blocking NF-B activation or induction of heat shock protein expression, which may allow cells to resist higher temperatures and other toxic agents as well as prevent leukemia cell apoptosis (13-15). In contrast, proteasome inhibitors can also induce cancer cell apoptosis, accompanied by activation of several caspases, such as caspase-3 or caspase-7 (16, 17...

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“…Various classes of proteins interact with BRCA1, including: (1) components of the basal transcription machinery [e.g., RNA helicase A and RNA pol II (Anderson et al, 1998;Schlegel et al, 2000a)]; (2) generalized transcriptional coactivators [p300, CBP, Brg1 (Bochar et al, 2000;Pao et al, 2000)] and corepressors [e.g., RbAp46, RbAp48, histone deacetylases-1,2, and CtIP (Yarden and Brody, 1998;Yu et al, 1998)]; (3) tumor suppressors [e.g., p53, RB1, BRCA2 (Chen et al, 1998;Ouichi et al, 1998;Yarden and Brody, 1998;Zhang et al, 1998;Aprelikova et al, 1999;Chai et al, 1999;Fan et al, 2001c)]; (4) steroid hormone receptors, estrogen receptor-a, and androgen receptor (Yeh et al, 2000;Fan et al, 2001a); (5) DNA repair proteins [e.g., Rad51, Rad50, hMSH2 (Scully et al, 1997b;Zhong et al, 1999;Wang et al, 2001a)]; (6) other sequence-specific transcription factors [e.g., c-Myc, Oct-1, and NF-YA Fan et al, 2002b)]; and (7) cell cycle regulatory proteins [e.g., BARD1, E2F1, cyclins (Wu et al, 1996;Wang et al, 1997)]. These interactions are summarized in Figure 1; and the significance of these interactions is discussed in ''Functional Activities of BRCA1''.…”

Section: Brca1 Protein: Protein Interactionsmentioning

confidence: 99%

“…BRCA1 was found to interact directly with the AR and to stimulate the activity of several androgen response element (ARE) driven promoters in prostate cancer cells (Yeh et al, 2000). In particular, BRCA1 up-regulated the AR-mediated expression of p21 WAF/Cip1 .…”

Section: Regulation Of Transcriptionmentioning

confidence: 99%

BRCA1 gene in breast cancer

Rosen

Fan

Pestell

et al. 2003

Journal Cellular Physiology

233

189

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The BRCA1 gene was identified and cloned in 1994 based on its linkage to early onset breast cancer and breast-ovarian cancer syndromes in women. While inherited mutations of BRCA1 are responsible for about 40-45% of hereditary breast cancers, these mutations account for only 2-3% of all breast cancers, since the BRCA1 gene is rarely mutated in sporadic breast cancers. However, BRCA1 expression is frequently reduced or absent in sporadic cancers, suggesting a much wider role in mammary carcinogenesis. Since BRCA1 was cloned in 1994, its molecular function has been the subject of intense investigation. These studies have revealed multiple functions of the BRCA1 that may contribute to its tumor suppressor activity, including roles in: cell cycle progression, several highly specialized DNA repair processes, DNA damage-responsive cell cycle checkpoints, regulation of a set of specific transcriptional pathways, and apoptosis. Many of these functions are linked to protein:protein interactions involving different portions of the 1,863 amino acid (aa) BRCA1 protein. BRCA1 functions in cell cycle progression and the DNA damage response appear to be regulated by distinct and specific phosphorylation events, but the molecular pathways activated by these phosphorylations are only beginning to be unraveled. In addition, the reason that BRCA1 mutation carriers develop specific tumor types (breast and ovarian cancers in women and possibly prostate cancers in men) is not clearly understood. Elucidation of the precise molecular functions of the BRCA1 gene product will greatly enhance our understanding of the pathogenesis of hereditary as well as sporadic mammary carcinogenesis.

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Increase of androgen-induced cell death and androgen receptor transactivation by BRCA1 in prostate cancer cells

Cited by 136 publications

References 51 publications

BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells

BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells

Proteasome Activity Is Required for Androgen Receptor Transcriptional Activity via Regulation of Androgen Receptor Nuclear Translocation and Interaction with Coregulators in Prostate Cancer Cells

BRCA1 gene in breast cancer

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