DNA methyltransferase inhibitor 5‐aza‐CdR enhances the radiosensitivity of gastric cancer cells

Qian, Hong; Yashiro, Masakazu; Shinto, Osamu; Matsuzaki, Taro; Hirakawa, Kosei

doi:10.1111/j.1349-7006.2008.01004.x

Cited by 51 publications

(68 citation statements)

References 29 publications

(37 reference statements)

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“…This unique characteristic has sparked enormous interest on the potential application of epigenetic drug, such as the Food and Drug administration-approved 5-aza-1 2′-deoxycytidine (5-aza-dC), 9 in gastric cancer patients. This notion is supported by multiple lines of in vitro evidence that 5-aza-dC can markedly increase the chemo-and radiosensitivity of different CpG island methylator phenotype gastric cancer cells, 5,10,11 and a recent in vivo study reporting the cancer chemopreventive effect of 5-aza-dC in gerbils infected with a stomach carcinogen Helicobacter pylori (H. pylori). 12 Nevertheless, the mechanistic actions of 5-aza-dC in gastric carcinogenesis remained incompletely understood, questioning the therapeutic value of epigenetic drug in this disease.…”

Section: Introductionmentioning

confidence: 87%

Epigenetic silencing of GDF1 disrupts SMAD signaling to reinforce gastric cancer development

Yang

Mok

et al. 2015

Oncogene

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Accumulating evidence reveals the effectiveness of epigenetic therapy in gastric cancer. However, the molecular mechanisms and targets underlying such therapeutic responses remain elusive. Herein, we report an aberrant yet therapeutically rectifiable epigenetic signaling in gastric carcinogenesis. Administration of DNA-demethylating drug 5-aza-2'-deoxycytidine (5-aza-dC) reduced gastric cancer incidence by ~74% (P < 0.05) in N-nitroso-N-methylurea-treated mice. Through genome-wide methylation scanning, novel promoter hypermethylation-silenced and drug-targeted genes were identified in the resected murine stomach tumors and tissues. We uncovered that growth/differentiation factor 1 (Gdf1), a member of the transforming growth factor-β superfamily, was silenced by promoter hypermethylation in control tumor-bearing mice, but became reactivated in 5-aza-dC-treated mice (P < 0.05). In parallel, the downregulated SMAD2/3 phosphorylation in gastric cancer was revived by 5-aza-dC in vivo. Such hypermethylation-dependent silencing and 5-aza-dC-mediated reactivation of GDF1-SMAD2/3 activity was conserved in human gastric cancer cells (P < 0.05). Subsequent functional characterization further revealed the antiproliferative activity of GDF1, which was exerted through activation of SMAD2/3/4-mediated signaling, transcriptional controls on p15, p21 and c-Myc cell-cycle regulators and phosphorylation of retinoblastoma protein. Clinically, hypermethylation and loss of GDF1 was significantly associated with reduced phosphorylated-SMAD2/3 and poor survival in stomach cancer patients (P < 0.05). Taken together, we demonstrated a causal relationship between DNA methylation and a tumor-suppressive pathway in gastric cancer. Epigenetic silencing of GDF1 abrogates the growth-inhibitory SMAD signaling and renders proliferation advantage to gastric epithelial cells during carcinogenesis. This study lends support to epigenetic therapy for gastric cancer chemoprevention and identifies a potential biomarker for prognosis.

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Section: Introductionmentioning

confidence: 87%

Epigenetic silencing of GDF1 disrupts SMAD signaling to reinforce gastric cancer development

Yang

Mok

et al. 2015

Oncogene

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“…OCUM-2MLN (Fujihara et al, 1999) and OCUM-12 (Qiu et al, 2009) were derived from scirrhous gastric carcinomas. MKN-45 (Motoyama et al, 1986) and MKN-74 (Motoyama et al, 1986) were derived from non-scirrhous gastric carcinomas.…”

Section: Cell Linesmentioning

confidence: 99%

Inhibitory effect of a TGFβ receptor type-I inhibitor, Ki26894, on invasiveness of scirrhous gastric cancer cells

et al. 2010

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BACKGROUND: Gastric cancer cells frequently metastasise, partly because of their highly invasive nature. Transforming growth factor-b (TGF-b) receptor signalling is closely associated with the invasion of cancer cells. The aim of this study was to clarify the effect of a TGF-b receptor (TbR) phosphorylation inhibitor on the invasiveness of gastric cancer cells. METHODS: Four gastric cancer cell lines, including two scirrhous-type cell lines and two non-scirrhous-type cell lines, were used. A TbR type I (TbR-I) kinase inhibitor, Ki26894, inhibits the phosphorylation of Smad2 at an ATP-binding site of TbR-I. We investigated the expression levels of TbR and phospho-Smad2, and the effects of TGF-b in the presence or absence of Ki26894 on Smad2 phosphorylation, invasion, migration, epithelial-to-mesenchymal transition (EMT), Ras homologue gene family member A (RhoA), ZO-2, myosin, and E-cadherin expression of gastric cancer cells. RESULTS: TbR-I, TbR-II, and phospho-Smad2 expressions were found in scirrhous gastric cancer cells, but not in non-scirrhous gastric cancer cells. Ki26894 decreased Smad2 phosphorylation induced by TGF-b1 in scirrhous gastric cancer cells. Transforming growth factor-b1 upregulated the invasion, migration, and EMT ability of scirrhous gastric cancer cells. Transforming growth factor-b1 significantly upregulated the activity of RhoA and myosin phosphorylation, whereas TGF-b1 decreased ZO-2 and E-cadherin expression in scirrhous gastric cancer cells. Interestingly, Ki26894 inhibited these characteristics in scirrhous gastric cancer cells. In contrast, non-scirrhous gastric cancer cells were not affected by TGF-b1 or Ki26894 treatment. CONCLUSION: A TbR-I kinase inhibitor decreases the invasiveness and EMT of scirrhous gastric cancer cells. Ki26894 is therefore considered to be a promising therapeutic compound for the metastasis of scirrhous gastric carcinoma.

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“…[9][10][11] However, there are a few reports on the radiosensitivity associated with exposure to DAC. [12][13][14][15] The present study, therefore, examined the effect of DAC on the radiation sensitivity of breast cancer cells.…”

Section: Introductionmentioning

confidence: 99%

5-aza-2′-Deoxycytidine Enhances the Radiosensitivity of Breast Cancer Cells

Wang

Zhang

et al. 2013

Cancer Biotherapy and Radiopharmaceuticals

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DNA methyltransferase inhibitor 5‐aza‐CdR enhances the radiosensitivity of gastric cancer cells

Cited by 51 publications

References 29 publications

Epigenetic silencing of GDF1 disrupts SMAD signaling to reinforce gastric cancer development

Epigenetic silencing of GDF1 disrupts SMAD signaling to reinforce gastric cancer development

Inhibitory effect of a TGFβ receptor type-I inhibitor, Ki26894, on invasiveness of scirrhous gastric cancer cells

5-aza-2′-Deoxycytidine Enhances the Radiosensitivity of Breast Cancer Cells

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