Differential requirement of signal pathways for benzo[a]pyrene (B[a]P)-induced nitric oxide synthase (iNOS) in rat esophageal epithelial cells
Differential requirement of signal pathways for benzo[a]pyrene (B[a]P)-induced nitric oxide synthase (iNOS) in rat esophageal epithelial cells
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DOI：
10.1093/carcin/bgi052
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发表时间：
2005-06-01
期刊：
影响因子：
4.7
通讯作者：
Huang, CS
中科院分区：
文献类型：
--
作者：
Chen, JY;Yan, Y;Huang, CS
诱导型一氧化氮合酶（iNOS）的过表达已被报道在几种人类癌症，包括食管鳞状细胞癌（SCC）。苯并[a]芘（B[a]P）是一种多环烃类致癌物，存在于烟草烟雾和环境中，可在动物多个器官部位诱发癌症，并可能是某些人类癌症（如食道癌）的致病因子。在本研究中，B[a]P对诱导的诱导型一氧化氮合酶的影响和导致诱导的信号通路在培养的大鼠食管上皮细胞（RE-149）进行了研究。用B[a]P处理RE-149细胞导致iNOS表达显著增加。发现B[a]P对iNOS的诱导是通过细胞外信号调节蛋白激酶（ERK）依赖性途径发生的，因为通过用ERK上游激酶MEK 1/2的抑制剂PD 98059预处理RE-149细胞或过表达DN-ERK 2来抑制ERK，阻断了B[a] P对iNOS的诱导。核损伤因子-κ B通过NEMO-BDBP（一种NF κ B特异性抑制剂）或DN-I κ B α或IKK-KM的过表达激活NF κ B，显著抑制B[a] P诱导的iNOS的表达，提示NF κ B途径也是B[a] P诱导iNOS所必需的。此外，用SB 202190（p38激酶抑制剂）或c-JunN末端激酶抑制剂II处理RE-149细胞，导致iNOS诱导增加。用PI-3 K抑制剂wortmannin或mTOR/p70 S6 K通路抑制剂rapamycin预处理RE-149细胞对iNOS的表达没有影响。这些结果表明，B[a]P启动的信号通路，导致诱导的iNOS在培养的大鼠食管上皮细胞。鉴于诱导型一氧化氮合酶在人类食管鳞状细胞癌发生中的潜在作用，我们推测B[a]P诱导诱导型一氧化氮合酶可能是B[a]P在人类食管中产生致癌作用的机制之一。
Overexpression of inducible nitric oxide synthase (iNOS) has been reported in several human cancers, including esophageal squamous cell carcinoma (SCC). Benzo[a]pyrene (B[a]P), a polycyclic hydrocarbon carcinogen found in tobacco smoke and in the environment, induces cancer in multiple organ sites in animals and may be a causative agent for certain human cancers, such as esophageal cancer. In the present study, the effects of B[a]P on the induction of iNOS and the signaling pathways that lead to the induction were investigated in cultured rat esophageal epithelial (RE-149) cells. Treatment of RE-149 cells with B[a]P led to a marked increase in the expression of iNOS. The induction of iNOS by B[a]P was found to occur through an extracellular signal-regulated protein kinases (ERKs)-dependent pathway, since inhibition of ERKs by either pretreatment of RE-149 cells with PD98059, an inhibitor of ERKs upstream kinase MEK1/2, or overexpression of DN-ERK2, blocked the induction of iNOS by B[a]P. Furthermore, impairing nuclear factor-kappa B (NF kappa B) activation by either NEMO-BDBP, an NF kappa B specific inhibitor, or overexpression of DN-I kappa B alpha or IKK-KM markedly inhibited the expression of B[a]P-induced iNOS, suggesting that the NF kappa B pathway is also required for the induction of iNOS by B[a]P. In addition, treatment of RE-149 cells with either SB202190, a p38 kinase inhibitor, or c-JunN-terminal kinase inhibitor II, resulted in an increased induction of iNOS. Pretreatment of RE-149 cells with wortmannin, a PI-3K inhibitor, or with rapamycin, an mTOR/p70S6K pathway inhibitor, had no effect on the expression of iNOS. These results suggest that B[a]P initiates the signaling pathways leading to the induction of iNOS in cultured rat esophageal epithelial cells. In view of the potential role of iNOS in the development of esophageal SCC in humans, we speculate that the induction of iNOS by B[a]P may be one mechanism by which B[a]P could produce carcinogenic effects in the human esophagus.