Blockade of Paclitaxel-Induced Thymidine Phosphorylase Expression Can Accelerate Apoptosis in Human Prostate Cancer Cells

Kikuno, Nobuyuki; Moriyama-Gonda, Nobuko; Yoshino, Tomoyuki; Yoneda, Tatsuaki; Urakami, Shinji; Terashima, Masaharu; Yoshida, Manabu; Kishi, Hirofumi; Shigeno, Kazushi; Shiina, Hìroaki; Igawa, Mikio

doi:10.1158/0008-5472.can-04-0996

Cited by 12 publications

(8 citation statements)

References 12 publications

(10 reference statements)

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“…The immunohistochemical staining was graded on an arbitrary scale from 0 to 2+; 0 representing negative expression (0–20% positive cells), 1+ representing weakly positive expression (20–50% positive cells) and 2+ representing strongly positive expression (50–100% positive cells). The scale was determined according to the average number of positive cells in 10 random fields of all slides 19…”

Section: Methodsmentioning

confidence: 99%

DNA methylation and histone modifications cause silencing of Wnt antagonist gene in human renal cell carcinoma cell lines

Kawamoto

Hirata

Kikuno

et al. 2008

Intl Journal of Cancer

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Secreted frizzled-related protein 2 (sFRP2) is a negative modulator of the Wingless-type (Wnt) signaling pathway, and shown to be inactivated in renal cell carcinoma (RCC). However, the molecular mechanism of silencing of sFRP2 is not fully understood. Our study was designed to elucidate the silencing mechanism of sFRP2 in RCC. Expression of sFRP2 was examined in 20 pairs of primary cancers by immunohistochemistry. Kidney cell lines (HK-2, Caki-1, Caki-2, A-498 and ACHN) were analyzed for sFRP2 expression using real-time RT-PCR and Western blotting. The methylation status at 46 CpG sites of the 2 CpG islands in the sFRP2 promoter was characterized by bisulfite DNA sequencing. Histone modifications were assessed by chromatin immunoprecipitation (ChIP) assay using antibodies against AcH3, AcH4, H3K4 and H3K9. sFRP2 was frequently repressed in primary cancers and in RCC cells. The majority of sFRP2 negative cells had a methylated promoter. Meanwhile, sFRP2 expression was repressed by a hypomethylated promoter in Caki-1 cells, and these cells had a repressive histone modification at the promoter. In Caki-1 cells, sFRP2 was reactivated by trichostatin A (TSA). Repressive histone modifications were also observed in RCC cells with hypermethylated promoters, but sFRP2 was reactivated only by 5-aza-2 0 -deoxycytidine (DAC) and not by TSA. However, the activation of the silenced sFRP2 gene could be achieved in all cells using a combination of DAC and TSA. This is the first report indicating that aberrant DNA methylation and histone modifications work together to silence the sFRP2 gene in RCC cells. ' 2008 Wiley-Liss, Inc.Key words: sFRP2 gene; Wnt antagonist; DNA methylation; histone modification; renal cell carcinoma Epigenetic mechanisms play a crucial role in regulation of gene expression, and different epigenetic processes are involved in gene silencing. 1 DNA methylation and histone modifications are 2 important reversible mechanisms of epigenetic regulation of gene expression. 2,3 Silencing of cancer-associated genes by hypermethylation of CpG islands within the promoter and/or 5 0 -regions is a common feature of human cancer and is often associated with partial or complete transcriptional block. 4 However, some genes are repressed without apparent hypermethylation at the promoters. 5,6 Histone modifications are another key player in epigenetics. 7 Deacetylation of H3 and H4, demethylation of H3 lysine 4 (H3K4) and methylation of H3 lysine 9 (H3K9) are markers of transcriptionally silent heterochromatin. 8 Today, histone modifications are recognized as playing a primary role in the control of gene expression and chromatin structure and are closely involved with DNA methylation. 7 These processes have been shown to be involved in the inactivation of many tumor suppressor genes. 9,10 sFRP2 is one such putative tumor suppressor gene. This gene is a negative modulator of the Wingless-type (Wnt) signaling pathway and its loss has been associated with aberrant activation of the Wnt signaling cascade. 11 Wnt antagonists, ...

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Section: Methodsmentioning

confidence: 99%

DNA methylation and histone modifications cause silencing of Wnt antagonist gene in human renal cell carcinoma cell lines

Kawamoto

Hirata

Kikuno

et al. 2008

Intl Journal of Cancer

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“…In fact, macrophages are known to produce multiple angiogenesis mediators, including cytokines that may up-regulate TPase transcription and enzyme activity, such as tumor necrosis factor-␣, interleukin-1, interferon-␥, and interferon-␣ (Goto et al, 2001;Zhu and Schwartz, 2003;De Bruin et al, 2004;Yao et al, 2005). In addition, hypoxia, low pH, and chemotherapeutic agents, including cyclophosphamide, oxaliplatin and taxanes, and X-ray radiation have been shown to increase TPase/PD-ECGF protein levels in various human tumors (Griffiths et al, 1997;Sawada et al, 1999;Kikuno et al, 2004, Toi et al, 2004.…”

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confidence: 99%

“…TPase thus protects cells from apoptosis induced by various cell-damaging agents, which has lead to the hypothesis that a combination of TPase-inducible chemotherapy with TPase-targeted treatment, such as fluorouracil derivatives, might enhance the effectiveness of anticancer therapy (Kikuno et al, 2004, Toi et al, 2004. A recent phase III trial on metastatic breast cancer has indeed shown that the addition of capecitabine to standard TPase-inducible chemotherapy like paclitaxel, cisplatin, cyclophosphamide, or irradiation results in increased response rate, time to progression, and survival of patients compared with standard treatment alone (Toi et al, 2005;Walko and Lindley, 2005).…”

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confidence: 99%

5′-O-Tritylated Nucleoside Derivatives: Inhibition of Thymidine Phosphorylase and Angiogenesis

Liekens¹,

Bronckaers²,

Hernández³

et al. 2006

Mol Pharmacol

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“…Finally, to examine whether SEPT10 expression was associated with clinical paclitaxel resistance, we performed immunohistochemical analysis on clinical specimens of ovarian carcinoma. It has reported that paclitaxel‐sensitive cancers show high‐level expression of caspase‐3 . Thus, we also examined expression of caspase‐3, a downstream effector of apoptosis, as an index of the specimens’ paclitaxel sensitivity.…”

Section: Resultsmentioning

confidence: 99%

“…It has reported that paclitaxel-sensitive cancers show high-level expression of caspase-3. (23) Thus, we also examined expression of caspase-3, a downstream effector of apoptosis, as an index of the specimens' paclitaxel sensitivity. As shown in Figure 5, SEPT10 and caspase-3 were strongly expressed in cytoplasm of paclitaxel-sensitive tumor cells.…”

Section: Resultsmentioning

confidence: 99%

Identification of a novel role of Septin 10 in paclitaxel‐resistance in cancers through a functional genomics screen

Takanashi

Oikawa

et al. 2012

Cancer Science

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Paclitaxel (also known as taxol) is a member of the taxane class of anticancer agents, which has a well-known mechanism that blocks cell mitosis and kills tumor cells, that is often used in clinics to treat cancer. However, some carcinomas such as breast, ovarian and non-small-cell lung cancers are often resistant to paclitaxel treatment. In this study, we used a lentiviral siRNA library against the entire human genomes to identify genes associated with sensitivity to paclitaxel. We isolated two paclitaxel-resistant clones carrying the siRNA specific to septin 10 (SEPT10) and to budding uninhibited by benzimidazoles 3. The relation of budding uninhibited by benzimidazoles 3 to paclitaxel sensitivity has already been established, but that of SEPT10 remains unknown. Interestingly, overexpression of SEPT10 increased cells' sensitivity to paclitaxel; we also found that SEPT10 is an important regulator for microtubule stability. Furthermore, we found that paclitaxel-resistant tumors had decreased expression of SEPT10. Thus, SEPT10 may be a novel candidate molecule that acts as a good indicator of paclitaxel-resistant carcinomas (Cancer Sci 2012; 103: 821-827)

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Blockade of Paclitaxel-Induced Thymidine Phosphorylase Expression Can Accelerate Apoptosis in Human Prostate Cancer Cells

Cited by 12 publications

References 12 publications

DNA methylation and histone modifications cause silencing of Wnt antagonist gene in human renal cell carcinoma cell lines

DNA methylation and histone modifications cause silencing of Wnt antagonist gene in human renal cell carcinoma cell lines

5′-O-Tritylated Nucleoside Derivatives: Inhibition of Thymidine Phosphorylase and Angiogenesis

Identification of a novel role of Septin 10 in paclitaxel‐resistance in cancers through a functional genomics screen

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