Mechanisms of gaseous nitric oxide promoting lung cancer(一)Formation of 8-NO2-G in MRC-5 cells(二)The signaling transduction pathway involvement of iNOS activation )

• Main Authors: HsueChun Wang, 王雪君
• Other Authors: Wang Chau-Jong
• Format: Others
• Language: zh-TW
• Published: 2000
• Online Access: http://ndltd.ncl.edu.tw/handle/77112889960328533969

碩士 === 中山醫學院 === 生物化學研究所 === 88 === Nitric oxide (NO) is a common indoor and outdoor environmental toxic pollutant arising from gas and wood-burning stoves, and emissions from auto-motive and other combustion engines. There is considerable evidence to suggest that NO-induced injury in mammalian lung cells. NO may cause DNA or tissue damage, contributing to the multistage carcinogenesis. We demonstrated that 8-nitroquanine was formed time- and dose- dependently in human lung fibroblast cells (MRC-5) exposed to gaseous NO. These results suggest that 8-nitroquanine could act as a specific marker for DNA damage induced by pollutant NO. In addition, exposure of isolated DNA in MRC-5 cells to gaseous NO led to 8-nitroquanine produce. NO induced DNA damage also led to p53 protein accumulation and phosphorylation. These results also indicated that gaseous NO directly attack DNA and partly induced endogenous NO by activating inducible nitric oxide synthase (iNOS). Many studies have identified NO as having a critical role in cellular signaling. In this study, we focused on elucidating the mechanism of gaseous NO signaling in MRC-5 cells. We found that NO-induced activation of inducible nitric oxide synthase (iNOS) led to sustained NO production, and MEKK1/MKK4/JNK MAPK pathway was involved in mediating NO signaling, inducing NF-κB/c-Jun/c-Fos activation. NO-induced MEKK1/MKK4/JNK activation was suppressed by the iNOS inhibitor, Nω-nitro-L-Arg-methyl ester. In addition, gaseous NO also caused STAT1 and Akt activation. These data support the hypothesis that critical signaling kinase, such as MEKK1, MKK4, JNK, NF-κB, c-Jun, c-Fos, STAT1, and Akt, are activated by NO and thus participate in NO signaling transduction. These findings elucidate multiple signaling pathways in the cellular response to gaseous NO.