5α‐dihydrotestosterone inhibits 1α,25‐dihydroxyvitamin D<sub>3</sub>‐induced expression of CYP24 in human prostate cancer cells

Lou, Yan-Ru; Nazarova, Nadja; Talonpoika, R.; Tuohimaa, Pentti

doi:10.1002/pros.20189

Cited by 20 publications

(17 citation statements)

References 40 publications

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“…CYP24 inhibitor can increase the calcitriol half-life in DU145 cells. Although calcitriol-induced levels of CYP24 mRNA are very dramatic compared with its basal levels, the CYP24 activity is low in LNCaP and PC3 cells, only 0.001% of DU145, and may not be sufficient to cause a significant change in the catabolism of calcitriol (26). Several calcitriol-based combination therapies also showed that CYP24 mRNA abundance is not always associated with the CYP24 activity (42).…”

Section: Discussionmentioning

confidence: 99%

“…Upon establishing that 10 nmol/L calcitriol combined with 10 Amol/L VES exhibited significant growth inhibition, the following VDR target genes were analyzed under the same experimental conditions. CYP24, containing two VDREs in the promoter, is one of the well-studied calcitriol target genes and is highly inducible by calcitriol in prostate cancer cells (26). It has been shown that induction of CYP24 mRNA can serve as an indicator of calcitriol-mediated genomic activity (27).…”

Section: Translational Relevancementioning

confidence: 99%

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RRR-α-Vitamin E Succinate Potentiates the Antitumor Effect of Calcitriol in Prostate Cancer without Overt Side Effects

Yin

Chen

et al. 2008

Clinical Cancer Research

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Purpose: To determine the antitumor efficacy of using calcitriol combined with RRR-a-vitamin E succinate (VES) on prostate cancer. Experimental Design: The effects of VES or VES in combination with calcitriol on the calcitriol target genes were evaluated by Western blot and real-time PCR. The antiproliferation effect of the combination in prostate cancer cells was evaluated by the combination index method. The role of the vitamin D 3 receptor (VDR) in the enhanced antitumor effects of the combination was confirmed by small interfering RNA knockdown strategy. Xenograft-bearing mice were used to reaffirm the antitumor efficacy of this combination. Pathohistology analyses and expressions of VDR and its target genes were analyzed in untreated and treated tumors. Results: VES selectively increased VDR protein in different prostate cancer cells. Low doses of calcitriol combined with VES were significantly superior to the additive effect of individual treatments against prostate cancer cell proliferation. The expression of VDR target genes involved in antiproliferation were further sensitized in the presence of VES. Knockdown of VDR expression abolished the combination benefits in LNCaP and PC3 cells. Consistently, in prostate cancer xenograft models,VES enhanced the therapeutic efficacy of a tolerated dose of calcitriol yet without overt evidence of systemic toxicity and hypercalcemia. This notable in vivo effect was also accompanied by up-regulation of VDR target genes. Conclusions: Low-dose calcitriol combined with vitamin E analogue could be a solution to the calcemic side effect. The demonstration of superior antitumor activity of low-dose calcitriol plus VES provides the preclinical basis for developing a useful therapeutic strategy for prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Translational Relevancementioning

confidence: 99%

RRR-α-Vitamin E Succinate Potentiates the Antitumor Effect of Calcitriol in Prostate Cancer without Overt Side Effects

Yin

Chen

et al. 2008

Clinical Cancer Research

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“…38 Androgen binding to AR has been reported to slow the degradation of AR leading to prolonged androgen action. 29 A recent study by Lou et al 45 demonstrated that androgens can strongly inhibit calcitriol-induced 24-hydroxylase gene expression and retard the catabolism of calcitriol thus enhancing calcitriol actions in LNCaP cells. Furthermore, the coexistence of functional hormone response elements within the IGFBP-3 promoter 17,23 may act as a hormone response unit with shared accessory elements and accessory factors causing the synergistic transcriptional responses.…”

Section: Discussionmentioning

confidence: 99%

The role of insulin‐like growth factor binding protein‐3 in the growth inhibitory actions of androgens in LNCaP human prostate cancer cells

Peng

Wang

Malloy

et al. 2007

Intl Journal of Cancer

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Insulin-like growth factor binding protein-3 (IGFBP-3), an antiproliferative and proapoptotic protein, has been shown to be upregulated by growth inhibitory concentrations of androgens in LNCaP human prostate cancer (PCa) cells, but the mechanism of regulation and the role of IGFBP-3 in the modulation of PCa cell proliferation are unknown. In this study, we have examined the effects of a range of concentrations of the synthetic androgen R1881 on IGFBP-3 expression and cell growth in LNCaP cells. We have also investigated the role of androgen-stimulated IGFBP-3 in androgen-induced growth inhibition. We show that low doses of R1881 stimulate LNCaP cell proliferation, but do not induce IGFBP-3 expression, whereas high doses of R1881 that inhibit cell growth, significantly increase expression of IGFBP-3. Importantly, we demonstrate that the combination of calcitriol and androgens not only synergistically upregulates IGFBP-3 expression but also inhibits cell growth better than either hormone alone. siRNA knockdown of IGFBP-3 expression partially reverses the growth inhibition by calcitriol and by androgens. Furthermore, we find that the growth inhibitory dose of R1881 leads to increases in the cyclin dependent kinase inhibitors (CDKIs), p21 and p27 as well as to G1 arrest. These changes can be blocked or partially reversed by IGFBP-3 siRNA, indicating that the induction of CDKIs is downstream of IGFBP-3. Our data suggest, for the first time, that IGFBP-3 is involved in the antiproliferative action of high doses of androgens partly through p21 and p27 pathways and that IGFBP-3 may contribute significantly to androgen-induced changes in LNCaP cell growth. ' 2007 Wiley-Liss, Inc.

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“…The effect of 1␣,25-(OH) 2 D 3 has been studied in prostate cancer cells [11][12][13]. However, 1␣,25-(OH) 2 D 3 exhibits antiproliferative effect only at pharmacological concentrations and may cause hypercalcemia and hypercalciuria, which limit its therapeutic use [14,15].…”

Section: Introductionmentioning

confidence: 99%

Androgen enhances the antiproliferative activity of Vitamin D3 by suppressing 24-hydroxylase expression in LNCaP cells

Lou

Tuohimaa

2006

The Journal of Steroid Biochemistry and Molecular Biology

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5α‐dihydrotestosterone inhibits 1α,25‐dihydroxyvitamin D₃‐induced expression of CYP24 in human prostate cancer cells

Cited by 20 publications

References 40 publications

RRR-α-Vitamin E Succinate Potentiates the Antitumor Effect of Calcitriol in Prostate Cancer without Overt Side Effects

RRR-α-Vitamin E Succinate Potentiates the Antitumor Effect of Calcitriol in Prostate Cancer without Overt Side Effects

The role of insulin‐like growth factor binding protein‐3 in the growth inhibitory actions of androgens in LNCaP human prostate cancer cells

Androgen enhances the antiproliferative activity of Vitamin D3 by suppressing 24-hydroxylase expression in LNCaP cells

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5α‐dihydrotestosterone inhibits 1α,25‐dihydroxyvitamin D3‐induced expression of CYP24 in human prostate cancer cells

Cited by 20 publications

References 40 publications

RRR-α-Vitamin E Succinate Potentiates the Antitumor Effect of Calcitriol in Prostate Cancer without Overt Side Effects

RRR-α-Vitamin E Succinate Potentiates the Antitumor Effect of Calcitriol in Prostate Cancer without Overt Side Effects

The role of insulin‐like growth factor binding protein‐3 in the growth inhibitory actions of androgens in LNCaP human prostate cancer cells

Androgen enhances the antiproliferative activity of Vitamin D3 by suppressing 24-hydroxylase expression in LNCaP cells

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5α‐dihydrotestosterone inhibits 1α,25‐dihydroxyvitamin D₃‐induced expression of CYP24 in human prostate cancer cells