著者

Jun Ye Yuping Li Takeki Hamasaki Noboru Nakamichi Takaaki Komatsu Taichi Kashiwagi Kiichiro Teruya Ryuhei Nishikawa Takeshi Kawahara Kazuhiro Osada Kazuko Toh Masumi Abe Huaize Tian Shigeru Kabayama Kazumichi Otsubo Shinkatsu Morisawa Yoshinori Katakura Sanetaka Shirahata

出版者

The Pharmaceutical Society of Japan

雑誌

Biological and Pharmaceutical Bulletin (ISSN:09186158)

巻号頁・発行日

vol.31, no.1, pp.19-26, 2008-01-01 (Released:2008-01-01)

参考文献数

86

被引用文献数

57 61

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Vascular endothelial growth factor (VEGF) is a key mediator of tumor angiogenesis. Tumor cells are exposed to higher oxidative stress compared to normal cells. Numerous reports have demonstrated that the intracellular redox (oxidation/reduction) state is closely associated with the pattern of VEGF expression. Electrolyzed reduced water (ERW) produced near the cathode during the electrolysis of water scavenged intracellular H2O2 and decreased the release of H2O2 from a human lung adenocarcinoma cell line, A549, and down-regulated both VEGF transcription and protein secretion in a time-dependent manner. To investigate the signal transduction pathway involved in regulating VEGF expression, mitogen-activated kinase (MAPK) specific inhibitors, SB203580 (p38 MAPK inhibitor), PD98059 (ERK1/2 inhibitor) and JNKi (c-Jun N-terminal protein kinase inhibitor) were applied. The results showed that only PD98059 blocks VEGF expression, suggesting an important role for ERK1/2 in regulating VEGF expression in A549 cells. As well, ERW inhibited the activation of extracellular signal-regulated kinase (ERK) in a time-dependent manner. Co-culture experiments to analyze in vitro tubule formation assay revealed that A549 cell-derived conditioned medium significantly stimulated the formation of vascular tubules in all analyzed parameters; tubule total area, tubule junction, number of tubules, and total tubule length. ERW counteracted the effect of A549 cell-conditioned medium and decreased total tube length (p<0.01). The present study demonstrated that ERW down-regulated VEGF gene transcription and protein secretion through inactivation of ERK.

著者

Yoshinori KATAKURA

出版者

Japan Society for Bioscience, Biotechnology, and Agrochemistry

雑誌

Bioscience, Biotechnology, and Biochemistry (ISSN:09168451)

巻号頁・発行日

vol.70, no.5, pp.1076-1081, 2006-05-23 (Released:2006-05-23)

参考文献数

26

被引用文献数

13

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Although dysfunctional telomeres and oncogenic or stressful stimuli are known to trigger cellular senescence in normal human diploid cells, the molecules and signaling network involved in the cellular senescence program are not fully understood. We have been trying to identify cellular senescence-inducing factors by various means. First, we screened for an extrinsic signal that can induce cellular senescence in human lung adenocarcinoma cell line A549, and identified transforming growth factor-β (TGF-β) as the cellular senescence-inducing factor. Cancer cells senesced by treatment with TGF-β impaired tumorigenicity both in vitro and in vivo, suggesting that cellular senescence functions as a tumor suppression mechanism. Next, we identified 86 independent senescence-associated genes by subtractive screening using A549-derived cell lines. Thirdly, we established novel cell lines (AST cells) from A549 cells exposed to mild oxidative stress. AST cells demonstrated functional impairment of telomerase due to perturbed subcellular localization of human telomerase reverse transcriptase, suggesting that mild oxidative stress might affect the cell fate of cancer cells. These results should provide insight into the molecular basis of the cellular senescence program.

著者

Yoshinori KATAKURA Eriko NAKATA Yukiko TABIRA Takumi MIURA Kiichiro TERUYA Toshie TSUCHIYA Sanetaka SHIRAHATA

出版者

(社)日本農芸化学会

雑誌

Bioscience, Biotechnology, and Biochemistry (ISSN:09168451)

巻号頁・発行日

vol.67, no.4, pp.815-821, 2003 (Released:2003-06-28)

参考文献数

23

被引用文献数

12

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We have previously reported that transforming growth factor β (TGF-β) triggers two independent senescence programs, 1) replicative senescence dependent upon telomere shortening and 2) premature senescence independent of telomere shortening, in the cell line of A549 human lung adenocarcinoma. In this study, we examined the possibility that cancer cell tumor phenotypes could be suppressed by forced senescence. We used A549 cells treated with TGF-β for a long time (over 50 days), where senescence was induced in a telomere-shortening-dependent or an independent way. Fully senescent A549 cells were elongated, acquired contact inhibition capabilities when reaching confluence, and secreted the senescence-associated cytokine IL-6. Furthermore, senescent A549 cells had no tumorigenicity in nude mice. These results indicate that the forced induction of senescence in cancer cells may be a novel and potentially powerful method for advancing anti-cancer therapy.