RIP1 potentiates BPDE-induced transformation in human bronchial epithelial cells through catalase-mediated suppression of excessive reactive oxygen species.
RIP1 potentiates BPDE-induced transformation in human bronchial epithelial cells through catalase-mediated suppression of excessive reactive oxygen species.
复制标题
DOI：
10.1093/carcin/bgt143
复制
发表时间：
2013-09
期刊：
影响因子：
4.7
通讯作者：
Qiong Wang;Wenshu Chen;Xiuling Xu;Bilan Li;Weiyang He;M. T. Padilla;Junho Jang;T. Nyunoya;S. Amin;Xia Wang;Y. Lin
中科院分区：
文献类型：
--
作者：
Qiong Wang;Wenshu Chen;Xiuling Xu;Bilan Li;Weiyang He;M. T. Padilla;Junho Jang;T. Nyunoya;S. Amin;Xia Wang;Y. Lin
细胞生存信号对癌细胞的恶性表型很重要。尽管受体相互作用蛋白1(RIP1)在细胞生存信号中的作用已有很好的文献记载，但RIP1是否直接参与癌症的发展还从未被研究过。在这份报告中，我们发现RIP1在人非小细胞肺癌和小鼠肺癌组织中的表达显著增加。香烟烟雾暴露小鼠肺组织中RIP1的表达显著增加。在人支气管上皮细胞(HBECs)中，香烟烟雾提取物或烟草特有致癌物苯并(A)芘的活性形式苯并[a]芘二醇环氧化物(BPDE)可显著诱导RIP1。在RIP1基因敲除的HBECs中，BPDE诱导的细胞毒性显著增强，这与细胞内活性氧(ROS)的诱导和丝裂原活化蛋白激酶(MAPK)的激活有关，包括c-jun氨基末端激酶(JNK)、细胞外信号调节激酶(ERK)和p38。清除ROS可抑制BPDE诱导的MAPK激活，抑制ROS或MAPKs可显著阻断BPDE诱导的细胞毒作用，提示ROS介导的MAPK激活参与了BPDE诱导的细胞死亡。在RIP1基因敲除的HBECs中，ROS还原酶过氧化氢酶以ERK和JNK依赖的方式失稳，应用过氧化氢酶有效地阻止了BPDE诱导的ROS积聚和细胞毒性。重要的是，当抑制RIP1的表达时，BPDE诱导的HBECs转化显著减少。综上所述，这些结果强烈表明RIP1具有致癌作用，它通过保护DNA损伤的细胞免受致癌物诱导的细胞毒性和过量产生ROS来促进恶性转化。
Cell survival signaling is important for the malignant phenotypes of cancer cells. Although the role of receptor-interacting protein 1 (RIP1) in cell survival signaling is well documented, whether RIP1 is directly involved in cancer development has never been studied. In this report, we found that RIP1 expression is substantially increased in human non-small cell lung cancer and mouse lung tumor tissues. RIP1 expression was remarkably increased in cigarette smoke-exposed mouse lung. In human bronchial epithelial cells (HBECs), RIP1 was significantly induced by cigarette smoke extract or benzo[a]pyrene diol epoxide (BPDE), the active form of the tobacco-specific carcinogen benzo(a)pyrene. In RIP1 knockdown HBECs, BPDE-induced cytotoxicity was significantly increased, which was associated with induction of cellular reactive oxygen species (ROS) and activation of mitogen-activated protein kinases (MAPKs), including c-jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38. Scavenging ROS suppressed BPDE-induced MAPK activation and inhibiting ROS or MAPKs substantially blocked BPDE-induced cytotoxicity, suggesting ROS-mediated MAPK activation is involved in BPDE-induced cell death. The ROS-reducing enzyme catalase is destabilized in an ERK- and JNK-dependent manner in RIP1 knockdown HBECs and application of catalase effectively blocked BPDE-induced ROS accumulation and cytotoxicity. Importantly, BPDE-induced transformation of HBECs was significantly reduced when RIP1 expression was suppressed. Altogether, these results strongly suggest an oncogenic role for RIP1, which promotes malignant transformation through protecting DNA-damaged cells against carcinogen-induced cytotoxicity associated with excessive ROS production.