https://scholars.lib.ntu.edu.tw/handle/123456789/477542
標題: | IL-6 inhibits apoptosis and retains oxidative DNA lesions in human gastric cancer AGS cells through up-regulation of anti-apoptotic gene mcl-1 | 作者: | MING-TSAN LIN Juan C.-Y. KING-JEN CHANG Chen W.-J. Kuo M.-L. |
公開日期: | 2001 | 出版社: | Oxford University Press | 卷: | 22 | 期: | 12 | 起(迄)頁: | 1947-1953 | 來源出版物: | Carcinogenesis | 摘要: | Apoptosis plays a critical role in maintaining genomic integrity by selectively removing the most heavily damaged cells from the population. Reactive oxygen species (ROS) and certain inflammatory cytokines are always elevated during the human carcinogenic process. However, the biological significance of the interplay between ROS and inflammatory cytokine remains elusive. This study demonstrates that interleukin-6 (IL-6) effectively protects gastric cancer cells from the apoptosis induced by hydrogen peroxide (H2O2). The cell death signaling JNK pathway elicited by H2O2 is also inhibited by IL-6. We further found that Mcl-1, but not other Bcl-2 family members, was up-regulated by IL-6, by a substantial level over 24 h. We further transfected a mcl-1 expression vector, pCMV-mcl-1, into the AGS cells, and successfully obtained several mcl-1-overexpressing clones. Flow cytometric analysis shows that these mcl-1-overexpressing AGS cells are more resistant to the apoptosis induced by H2O2 when compared with the neo control AGS cells. Consistently, the activation of the JNK pathway induced by H2O2 is also blocked in mcl-1-overexpressed cells. These results indicate that the anti-apoptotic effect of IL-6 is, at least in part, due to the up-regulation of mcl-1. To our surprise, either IL-6 exposure or mcl-1 overexpression fails to reduce the level of intracellular peroxides in the AGS cells triggered by H2O2. This study also determined the level of 8-hydroxydeoxy-guanosine (8-OH-dGua), an indicator for oxidative DNA lesions in IL-6-treated or mcl-1-overexpressed AGS cells after treatment with H2O2. Notably, our results indicate that a majority of the 8-OH-dGua is efficiently removed in the AGS cells without IL-6 treatment, whereas only ?50% of the 8-OH-dGua was repaired in the IL-6-treated AGS cells after 24 h. Similarly, ?60-70% of the 8-OH-dGua also failed to repair and was retained in the genomic DNA of the mcl-1 transfectants. Results in this study provide a novel mechanism by which up-regulation of the Mcl-1 protein by IL-6 may enhance the susceptibility to H2O2-induced oxidative DNA lesions by overriding apoptosis. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-0035681366&doi=10.1093%2fcarcin%2f22.12.1947&partnerID=40&md5=849e8b4d5b1c61fd9f3896c340672cd1 https://scholars.lib.ntu.edu.tw/handle/123456789/477542 |
ISSN: | 0143-3334 | DOI: | 10.1093/carcin/22.12.1947 | SDG/關鍵字: | 8 hydroxydeoxyguanosine; DNA; hydrogen peroxide; interleukin 6; protein bcl 2; protein mcl 1; reactive oxygen metabolite; apoptosis; article; cancer cell; carcinogenesis; cell death; cell protection; controlled study; DNA damage; expression vector; flow cytometry; gene overexpression; genetic regulation; genetic transfection; human; human cell; oxidation; priority journal; stomach cancer |
顯示於: | 醫學系 |
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