Regulation of metallothionein and zinc transporter expression in human prostate cancer cells and tissues

Hasumi, Masaru; Suzuki, Kazuhiro; Matsui, Hiroshi; Koike, Hidekazu; Ito, Kazuto; Yamanaka, Hidetoshi

doi:10.1016/s0304-3835(03)00441-5

Cited by 87 publications

(69 citation statements)

References 24 publications

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“…Furthermore, our data are also consistent with the previous findings that the mechanistic actions of zinc is shown through change of the caspase enzymes activities, as well as the direct alteration of apoptotic regulators expression, especially the Bcl-2 family (29). In addition, abnormal expression of genes involved in zinc homeostasis has been described in breast carcinomas and tumors of other organs (30)(31)(32). Taken together, our findings have identified LIV1 as a novel target responsible for the action of HDACi.…”

Section: Discussionsupporting

confidence: 92%

Identification of LIV1, a Putative Zinc Transporter Gene Responsible for HDACi-Induced Apoptosis, Using a Functional Gene Screen Approach

Ma²,

Liu³

et al. 2009

Molecular Cancer Therapeutics

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Histone deacetylase inhibitors (HDACi) show promise as a novel class of antitumoral agents and have shown the ability to induce apoptosis of tumor cells. To gain a better understanding of the action of HDACi, we conducted a functional gene screen approach named suppression of mortality by antisense rescue technique to identify the key genes responsible for the tumor-selective killing trichostatin A. Over 20 genes associated with HDACiinduced mortality were identified. One of the confirmed positive hits is LIV1, a putative zinc transporter. LIV1 is significantly induced by treatment with HDACi in a number of tumor cells, but not in normal cells. Knockdown of LIV1 suppressed apoptosis induced by HDACi in tumor cells. Although HDACi induced a slight increase in the free intracellular zinc concentration, knockdown of LIV1 significantly enhanced the intracellular zinc level, which was associated with resistance to apoptosis. On the other hand, pretreatment of the cells with a specific zinc chelator TPEN reversed the apoptosis resistance conferred by knockdown of LIV1. However, the biological effects of TPEN were abolished by addition of physiologic concentrations of zinc. Taken together, the present study identifies LIV1 as a critical mediator responsible for HDACi-induced apoptosis. The effect of LIV1 is, at least in part, mediated by affecting intracellular zinc homeostasis, which may be related to alteration of the catalytic activity of the Caspase 3 and expression of some BCL-2 family genes. As such, these findings highlight a novel mechanism underlying the action of HDACi that could be potentially useful in the clinical setting.

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Section: Discussionsupporting

confidence: 92%

Identification of LIV1, a Putative Zinc Transporter Gene Responsible for HDACi-Induced Apoptosis, Using a Functional Gene Screen Approach

Ma²,

Liu³

et al. 2009

Molecular Cancer Therapeutics

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“…Detection of IGFBP-6 protein was performed according to modification of a previously described method (Hasumi et al, 2003). Equal amounts of proteins (100 mg) from PC-3 cells were electrophoresed on a 5 -20% SDS -polyacrylamide gel and transferred onto a nitrocellulose membrane.…”

Section: Detection Of Igfbp-6 Protein By Western Blottingmentioning

confidence: 99%

Insulin-like growth factor binding protein-6 inhibits prostate cancer cell proliferation: implication for anticancer effect of diethylstilbestrol in hormone refractory prostate cancer

et al. 2005

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Diethylstilbestrol (DES) is a synthetic oestrogen, and its anticancer effects are exerted in androgen-dependent prostate cancer. The administration of DES decreases serum testosterone to castration levels. However, in androgen-independent prostate cancer patients, who are already orchiectomised, the administration of DES improves symptoms and decreases prostate-specific antigen (PSA). The mechanisms responsible for these direct inhibitory effects have been explained as biological actions not mediated by oestrogen receptors. We assessed the gene expression profiles of prostate cancer cells treated with DES, and investigated direct inhibitory effects of DES. DES inhibited the proliferation of LNCaP and PC-3 cells. cDNA microarray analysis showed that expression of many genes was downregulated by DES. However, insulin-like growth factor binding protein 6 (IGFBP-6) gene expression levels were upregulated in PC-3 cells. IGFBP-6 gene expression and protein levels significantly increased after DES treatment. Recombinant IGFBP-6 inhibited cell proliferation, and the inhibitory effect of DES was neutralised by anti-IGFBP-6 antibody. From the immunohistochemical analysis of IGFBP-6 using biopsy samples from androgen-independent prostate cancer, we found IGFBP-6 expression in androgen independent prostate cancer, and that DES treatment increased the IGFBP-6 staining intensity of the cancer cells in one sample. These findings suggested that DES induces IGFBP-6, which inhibits cell proliferation in an androgen-independent prostate cancer cell line, PC-3. IGFBP-6 therefore might be involved in the direct effects of DES in androgen-independent prostate cancer. (Ferro et al, 1989), and diethylstilbestrol diphosphate (DESdP) is a nontoxic prodrug form of DES (Flocks et al, 1955;Abramson et al, 1982). The palliative effects of DESdP administered to advanced-, hormoneinsensitive prostate cancer patients are well known (Flocks et al, 1955;Colapinto et al, 1961;Band et al, 1973;Droz et al, 1994;Takezawa et al, 2001). DESdP relieves bone pain in the majority of patients with metastatic prostate cancer who receive therapy (Hawtrey et al, 1974;Takezawa et al, 2001).The administration of oestrogenic analogues causes the suppression of luteinising hormone-releasing-factor stimulation of the pituitary gland (Paulson, 1984). In addition, the subsequent reduction of testosterone synthesis induces anorchid levels of circulating serum testosterone (Paulson, 1984). The beneficial effect of DES therapy for previously orchiectomised patients, however, indicates that DES may not operate solely through the pituitary -gonadal axis. Several studies have sought to define the mode of DES action on a cellular level. DES treatment inhibits the growth of primary cultures derived from benign hyperplasia and prostate carcinoma samples (Brehmer et al, 1972) as well as prostate cancer cell lines (Schulz et al, 1990). Intracellular localisation studies of DES inhibition have targeted mitochondrial adenosine triphosphate synthase (McEnery et al, 1989), respir...

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“…Zinc transporters are classified as the ZnT and ZIP families, belonging to the solute-linked carrier (SLC) gene families SLC30 and SLC39, respectively. SLC30A1 and SLC30A4 expression was reported to be decreased in patients with prostate cancer compared to those with benign prostatic hyperplasia (8,9). SLC39A1 and SLC39A2 expression in prostate tumor tissues obtained from African-American patients was lower compared to that in Caucasian patients (10).…”

Section: Introductionmentioning

confidence: 95%

Suppression of metallothionein 3 gene expression by androgen in LNCaP prostate cancer cells

et al. 2013

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Abstract. Androgen deprivation therapy is the standard treatment for prostate cancer. However, tumors often progress towards a more aggressive phenotype despite treatment. Prostate tissue has a high zinc concentration, which may correlate with prostate cancer progression. Therefore, we investigated the effect of dihydrotestosterone (DHT) on the gene expression of metallothioneins (MTs) and zinc transporters in prostate cancer with quantitative real-time polymerase chain reaction (PCR). The MT3 gene expression in LNCaP cells was suppressed by DHT in a dose-dependent manner. However, it increased in a culture medium containing androgen-deficient charcoal-stripped fetal bovine serum (FBS). Bicalutamide, an androgen receptor antagonist, increased the gene expression of MT3 and partially reversed the suppression of MT3 gene expression induced by DHT. In PC-3 cells lacking androgen receptors, DHT and bicalutamide exerted no effect on MT3 gene expression. The reporter gene assay with a luciferase reporter plasmid containing the 5'-flanking region of MT3 demonstrated a decrease in luciferase activity caused by DHT that was reversed by bicalutamide. These results suggest that MT3 gene expression is downregulated by androgen.

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Regulation of metallothionein and zinc transporter expression in human prostate cancer cells and tissues

Cited by 87 publications

References 24 publications

Identification of LIV1, a Putative Zinc Transporter Gene Responsible for HDACi-Induced Apoptosis, Using a Functional Gene Screen Approach

Identification of LIV1, a Putative Zinc Transporter Gene Responsible for HDACi-Induced Apoptosis, Using a Functional Gene Screen Approach

Insulin-like growth factor binding protein-6 inhibits prostate cancer cell proliferation: implication for anticancer effect of diethylstilbestrol in hormone refractory prostate cancer

Suppression of metallothionein 3 gene expression by androgen in LNCaP prostate cancer cells

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