Effect of selective estrogen receptor modulators on cell proliferation and estrogen receptor activities in normal human prostate stromal and epithelial cells

Nomura, Hiroichi; Kawashima, Hidenori; Masaki, Sakae; Hosono, Tatsuya; Matsumura, K; Tamada, Satoshi; Tanaka, Tomoaki; Nakatani, Tatsuya

doi:10.1038/pcan.2009.20

Cited by 15 publications

(11 citation statements)

References 39 publications

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“…Based on the results of both MTT assay and FACS analysis, TAM exerted a much higher apoptotic activity compared to MIF. Very recently, it was reported that the ER-mediated pathway plays a central role in the growth of normal prostate cells [13]. This finding may support the high cytotoxicity of TAM against DU-145 cells found in the present study.…”

Section: Discussionsupporting

confidence: 91%

“…Recent reports have shown that TAM inhibits the proliferation and induces apoptosis not only in estrogen receptor (ER)-positive breast cancer cells, but also in ER-neg-ative breast cancer cells and other cancer cells; i.e., prostate cancer, ovarian cancer, colorectal cancer, and brain cancer [1,13,17]. Non-genomic effects of TAM has been suggested in many cell lines; including the inhibition of protein kinase C [3], interferences with the function of ion channels [7], and the activation of extracellular signal-regulated kinase (ERK1/2) [23].…”

Section: Introductionmentioning

confidence: 99%

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Effects of Mifepristone and Tamoxifen on Calcium Modulation in DU-145 Prostate Cancer Cells

Kim¹,

Kim²

2010

Journal of Life Science

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Mifepristone (MIF) and Tamoxifen (TAM) have been used in the treatment of prostate cancer and breast cancer for more than a decade. MIF can induce apoptosis in both AR-positive and -negative prostate cancer cells. Because of its pleiotropic ligand-receptor properties, TAM exerts cytotoxic activity in estrogen (ER)-positive and various ER-negative cancer cells. However, the molecular mechanisms of these two substances are not yet clear. In the present work, we report that the cytotoxic effects of MIF and TAM are due to the modulation of intracellular Ca 2+ level in DU-145, androgen-insensitive cells. When the cells were treated with micromolar concentrations of either MIF or TAM, the growth and viability were significantly decreased in a dose-and time-dependent manner. The apoptosis induced by MIF or TAM was further proved and analyzed by confocal laser scanning microscopy (CLSM) and fluorescence-activated cell sorting (FACS). In the cells cultivated in a normal 1.5 mM Ca 2+ medium, both MIF and TAM also induced an increase of the intracellular Ca 2+ level in a dose-dependent fashion. Since a change in calcium level could not be found in cells of the Ca 2+ -free medium, the increase of intracellular Ca 2+ level might be due to an increase in extracellular calcium uptake. Our results show that the apoptotic effect was more prominent in TAM treatment compared to MIF treatment in DU-145 cells. The above findings might be due to the difference in the uppermost pathways of apoptosis induced by either MIF or TAM. When we checked the level of procaspase-8 activation, TAM showed minor level of activation, as opposed to MIF, which exerted strong activation. In both treatments, the levels of anti-apoptotic protein Bcl-2 decreased, and pro-apoptotic protein Bax level increased more than 2-fold. The activation of caspase-3, a key protease enzyme in the downstream pathway of apoptosis, was much higher in the cells treated with TAM, compared to the MIF treatment. The overall apoptotic activity shown in the present work was closely related to intracellular Ca 2+ concentration levels. Therefore, the cytotoxic activity induced by MIF and TAM might have been due to intracellular calcium modulation.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Effects of Mifepristone and Tamoxifen on Calcium Modulation in DU-145 Prostate Cancer Cells

Kim¹,

Kim²

2010

Journal of Life Science

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“…However, most men who take combination therapy do not get any added benefit while additional four out of hundred patients face the risk of becoming impotent [55]. In view of recent studies indicating the importance of ER-mediated pathways in the pathogenesis of BPH [56,57]; selective modulation of estrogen receptor action offers an alternative and promising approach for the management of prostate disease. The in vivo data of present study clearly indicates the potential of SERMs in regulating prostatic size, which could be amplified further by combined 5α-reductase inhibition.…”

Section: Discussionmentioning

confidence: 99%

Selective estrogen receptor modulators regulate stromal proliferation in human benign prostatic hyperplasia by multiple beneficial mechanisms—action of two new agents

et al. 2010

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The existing drugs for benign prostatic hyperplasia (BPH) are partially effective with undesirable side-effects; hence new agents acting by different mechanism(s) are required as supplements. Modulation of estrogen receptor signaling using selective estrogen receptor modulators (SERMs) offers an alternative approach for BPH management. Using human BPH-derived stromal cells and tissue explants in culture we evaluated two SERMs, DL-2-[4-(2-piperidinoethoxy)phenyl]-3-phenyl-2 H-1-benzopyran (BP) and Ormeloxifene (Orm) in comparison to Tamoxifen (Tam) and 4-hydroxytamoxifen (OHT). BP, OHT and Tam were more effective than Orm in reducing stromal cell proliferation of human BPH. BP was either equipotent or more effective than OHT and Tam in increasing estrogen receptor(ER)-ß, TGFß1, Fas and FasL, and in decreasing ER-α, AR, EGF-R and IGF-I expressions in BPH stromal cells. BP, Tam and Orm (1.0 mg/Kg) reduced rat prostate weights by almost same extent as Finasteride (Fin, 5.0 mg/Kg); however combination treatment (SERM+Fin) was more effective. BP was exceptionally efficient in reducing IGF-1 and cleaving PARP while combination treatments more effectively increased bax:bcl-2 ratio. Fin reduced acinar diameter and prostatic DHT level but increased testosterone, estradiol (E(2)) and E(2)/T+DHT ratio. SERMs, especially BP, reduced epithelial cell height drastically without significantly altering steroid hormone levels and E(2)/T+DHT ratio. Combination treatment reduced both acinar diameter and epithelial cell height with modest increase in E(2), T and E(2)/T+DHT. The study reveals the potential of SERMs per se for BPH management, and more effectively in combination with a 5α-reductase inhibitor. BP appears promising for further evaluation as a drug candidate for BPH and prostate cancer.

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“…Zhong et al observed that ERK was activated by E2, causing the proliferation of PrSC, 22 whereas Nomura et al showed that toremifene, an ERa antagonist, strongly suppressed the ER activity and proliferation of primary PrSC. 23 Primary cultures of normal human prostatic epithelial and stromal cells have been used as useful models for studying the pathogenesis of BPH experimentally. However, the limitations of the prostatic primary cultures should also be considered; their proliferation rate is slow and they have a limited lifespan in culture, eventually undergoing senescence.…”

Section: Era As a Promoting Factor Of Bphmentioning

confidence: 99%

“…84 From a chemopreventative point of view, a clinical trial was carried out that showed that toremifene decreased the incidence of prostate cancer development in men with HGPIN. 85 Toremifene also strongly suppresses ER activity and cell proliferation in PrSC, 23 and the ability of toremifene to decrease the incidence of prostate cancer might be attributed to the suppression of the stromal paracrine that stimulates the precancerous lesion. Experimentally, toremifene suppressed prostate cancer development in the transgenic adenocarcinoma of mouse prostate model, 86 and delayed tumor formation and prolonged survival compared with placebo-treated animals.…”

Section: Er As a Therapeutic And Chemopreventative Target Of Prostatimentioning

confidence: 99%

Involvement of estrogen receptors in prostatic diseases

Kawashima

Nakatani

2012

Int J of Urology

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Abbreviations & Acronyms 3,4-QE2 = estradiol-3,4,quinone 3b-adiol = 5a-androstane-3b, 17b-diol 4-OHE2 = 4-hydroxyestradiol 17b-HSD VII = 17b-hydroxysteroid dehydrogenase type 7 AR = androgen receptor ArKO = aromatase-knockout BP = DL-2-[4-(2-piperidinoethoxy) phenyl]-3-phenyl-2 H-1-benzopyran BPH = benign prostatic hyperplasia CRPC = castration-resistant prostate cancer DES = diethylstilbestrol DHT = dihydrotestosterone E2 = estradiol EBAG9 = estrogen receptor-binding fragment-associated gene 9 EMT = epithelial-mesenchymal transition ER = estrogen receptor ERaKO = estrogen receptor a knockout ERbKO = estrogen receptor b knockout ERE = estrogen-responsive element ERG = v-ets erythroblastosis virus E26 oncogene homolog (avian) ERR = estrogen receptor-related receptors hERb = human estrogen receptor b HGPIN = high-grade prostatic intraepithelial neoplasia HIF-1a = hypoxia inducible factor 1a IGF-1 = insulin-like growth factor 1 KLF-5 = Krüppel-like zinc finger transcription factor 5 NFk = nuclear factor k NFkB = nuclear factor kB OHT = 4-hydroxytamoxifen PGC-1 = peroxisome proliferator-activated receptor g coactivator 1 PIN = prostatic intraepithelial neoplasia PrSC = prostatic stromal cells PSA = prostate-specific antigen RT-PCR = reverse transcription polymerase chain reaction SERM = selective estrogen receptor modulators TGFb = transforming growth factor b TMPRSS2 = transmembrane protease serine 2 VEGF-A = vascular endothelial growth factor A Abstract: Accumulating evidence shows that estrogens participate in the pathogenesis and development of benign prostatic hyperplasia and prostate cancer by activating estrogen receptor a. In contrast, estrogen receptor b is involved in the differentiation and maturation of prostatic epithelial cells, and thus possesses antitumor effects in prostate cancer. However, the natural ligands of estrogen receptor b are not fully understood , and its mode of action according to its ligands and the binding sites located in the promoter regions of downstream genes remains to be elucidated. Here, we review recent experimental investigations of estrogen receptors and their urological relevance. Estrogen receptor-mediated signaling in the prostate is essential together with the androgen receptor-mediated pathway, providing a new therapeutic target for prostatic diseases.

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Effect of selective estrogen receptor modulators on cell proliferation and estrogen receptor activities in normal human prostate stromal and epithelial cells

Cited by 15 publications

References 39 publications

Effects of Mifepristone and Tamoxifen on Calcium Modulation in DU-145 Prostate Cancer Cells

Effects of Mifepristone and Tamoxifen on Calcium Modulation in DU-145 Prostate Cancer Cells

Selective estrogen receptor modulators regulate stromal proliferation in human benign prostatic hyperplasia by multiple beneficial mechanisms—action of two new agents

Involvement of estrogen receptors in prostatic diseases

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