Human prostate tumor growth in athymic mice: inhibition by androgens and stimulation by finasteride.

Umekita, Yoshihisa; Hiipakka, Richard A.; Kokontis, John M.; Liao, Shutsung

doi:10.1073/pnas.93.21.11802

Cited by 176 publications

(145 citation statements)

References 29 publications

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“…Tumor growth was monitored every other day by caliper measurement. Tumor volumes were calculated using the formula length Â width Â height (Umekita et al, 1996). All animals were maintained in accordance with the European Union guidelines.…”

Section: Indirect Immunofluorescencementioning

confidence: 99%

Distinct roles for LINE-1 and HERV-K retroelements in cell proliferation, differentiation and tumor progression

et al. 2007

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Transformed cells express high levels of non-telomeric reverse-transcriptase (RT) activity of retrotransposon and endogenous retrovirus origin. We previously reported that RT inhibition, either pharmacological or through transient silencing of RT-encoding LINE-1 (L1) elements by RNA interference (RNAi), reduced proliferation, induced differentiation and reprogrammed gene expression in human tumorigenic cell lines. Moreover, the antiretroviral drug efavirenz antagonized tumor progression in animal models in vivo. To get insight into the role of retroelements in tumorigenesis, we have now produced two cell lines derived from A-375 melanoma, in which the expression of either L1 retrotransposon, or HERV-K endogenous retrovirus, was stably suppressed by RNAi. Compared to the parental A-375 cell line, cells with stably interfered L1 expression show a lower proliferation rate, a differentiated morphology and lower tumorigenicity when inoculated in nude mice. L1 silencing modulates expression of several genes and, unexpectedly, also downregulates HERV-K expression. In HERV-K interfered cells, instead, L1 expression was unaffected, and cell proliferation and differentiation remained unchanged compared to parental A-375 cells. In vivo, however, their tumorigenic potential was found to be reduced after inoculation in nude mice. These results suggest that L1 and HERV-K play specific and distinct roles in cell transformation and tumor progression.

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Section: Indirect Immunofluorescencementioning

confidence: 99%

Distinct roles for LINE-1 and HERV-K retroelements in cell proliferation, differentiation and tumor progression

et al. 2007

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“…AR and PSA protein expression was determined by immunoblotting using anti-AR (AN-21) and anti-PSA (DAKO, Elostrup, Denmark) antibodies as described previously [19][20][21][22][23][24].…”

Section: Western Blotting Analysismentioning

confidence: 99%

“…These androgen-independent LNCaP cells have elevated AR expression and express PSA upon androgen treatment. Androgens paradoxically inhibit the proliferation of these androgen-independent prostate cancer cells [20][21][22][23][24], which is relieved after knockdown or loss of AR expression [21,23,24]. Elevation of AR expression is often observed in advanced prostate tumors in patients [25,26].…”

Section: Introductionmentioning

confidence: 99%

“…T0901317 treatment in athymic mice delays the progression of prostate tumors towards androgen-independency [24]. Since AR and AR signaling is very important for proliferation and progression of prostate cancer cells [19][20][21][22][23][24][25][26][27] and LXR agonist T0901317 suppresses proliferation and progression of prostate cancer cells [15,24], we determined if T0901317 interacts with androgen receptor and if T0901317 affects AR signaling. …”

Section: Introductionmentioning

confidence: 99%

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The liver X receptor agonist T0901317 acts as androgen receptor antagonist in human prostate cancer cells

Chuu

Chen

Hiipakka

et al. 2007

Biochemical and Biophysical Research Communications

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T0901317 is a potent non-steroidal synthetic liver X receptor (LXR) agonist. T0901317 blocked androgenic stimulation of the proliferation of androgen-dependent LNCaP 104-S cells and androgenic suppression of the proliferation of androgen-independent LNCaP 104-R2 cells, inhibited the transcriptional activation of an androgen-dependent reporter gene by androgen, and suppressed gene and protein expression of prostate specific antigen (PSA), a target gene of androgen receptor (AR) without affecting gene and protein expression of AR. T0901317 also inhibited binding of a radiolabeled androgen to AR, but inhibition was much weaker compared to the effect of the antiandrogens, bicalutamide and hydroxyflutamide. The LXR agonist T0901317, therefore, acts as an antiandrogen in human prostate cancer cells.

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“…Although finasteride leads to much reduced intraprostatic DHT. it also results in substantially increased intraprostatic T levels (Norman et al 1993 (Umekita et al, 1996), suggests the possibility that it may also selectively stimulate PIN.…”

Section: Discussionmentioning

confidence: 99%

The effect of finasteride on the prostate gland in men with elevated serum prostate-specific antigen levels

Côté

Skinner²,

Salem³

et al. 1998

Br J Cancer

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Summary Prostate cancer is a disease associated with androgens. It has been hypothesized that reducing the conversion of testosterone (T) to dihydrotestosterone (DHT) in the prostate by the use of the drug finasteride. a 5a-reductase inhibitor, will reduce the incidence of prostate cancer. We investigated the chemopreventive potential of finasteride by evaluating its effect on the prostate gland of men with elevated serum prostate-specific antigen (PSA). Fifty-two men with elevated PSA and prostate sextant biopsies negative for cancer were randomized to receive finastende 5 mg day-, (27 patients) or no medication (25 patients) for 12 months and were rebiopsied at 12 months.The biopsies were evaluated for the presence of cancer, the proportion of glandular and hyperplastic tissue, and the presence of high-grade prostatic intraepithelial neoplasia (PIN). Epithelial proliferation was assessed in the prestudy and 12-month biopsies by immunohistochemistry using antibody to proliferating cell nuclear antigen (PCNA). Serum blood samples were drawn at baseline and after 1. 3, 6 and 12 months of study. In the control group, serum levels of PSA and T were unchanged throughout the 12 months. In the finastende group, PSA decreased 48°o (P < 0.001), DHT decreased 670o (P < 0.001) and T increased 21 0°(P < 0.001). Histological evaluation of prestudy and 12-month biopsy specimens revealed that the finasteride group had a 300% reduction in the percentage of hyperplastic epithelial tissue (P = 0.002). although this decrease was not statistically significantly different between the finasteride and control groups (P = 0.11). In patients with PIN on prestudy biopsy, no change occurred in the PIN lesions with finasterde treatment. Finasteride also had no effect on the proliferation index of prostatic epithelial cells. Of the 27 patients treated with finastende, eight (309O) had adenocarcinoma of the prostate detected on the 12-month biopsy. compared with one (40o) of the control patients (P = 0.025). In the treatment group, six cancers occurred in the eight patients with PIN on the prestudy biopsy: in the observation group no cancers were detected in the five patients with PIN on the prestudy biopsy (P= 0.021). Two cancers occurred in the 19 men in the treatment group with no evidence of PIN on the prestudy biopsy. compared with one cancer in the 20 men in the observation group with no evidence of PIN on the prestudy biopsy (P = 0.60). This study, using a novel model for evaluating short-term efficacy of chemopreventive or therapeutic agents in men at high nsk of prostate cancer. provides little evidence that finasteride is an effective chemopreventive agent for prostate cancer in men with elevated PSA. Keywords: finastende: prostate carcinoma: intraepithelial neoplasia: proliferation Carcinoma of the prostate is the most frequentl diagnosed cancer in the US. Although the most important risk factor for prostate cancer is age (Ross et al. 1979). there is also profound -ariation in incidence between different racial groups in the US....

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Human prostate tumor growth in athymic mice: inhibition by androgens and stimulation by finasteride.

Cited by 176 publications

References 29 publications

Distinct roles for LINE-1 and HERV-K retroelements in cell proliferation, differentiation and tumor progression

Distinct roles for LINE-1 and HERV-K retroelements in cell proliferation, differentiation and tumor progression

The liver X receptor agonist T0901317 acts as androgen receptor antagonist in human prostate cancer cells

The effect of finasteride on the prostate gland in men with elevated serum prostate-specific antigen levels

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