High levels of Nrf2 determine chemoresistance in type II endometrial cancer.
High levels of Nrf2 determine chemoresistance in type II endometrial cancer.
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DOI：
10.1158/0008-5472.can-10-0713
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发表时间：
2010-07-01
期刊：
影响因子：
11.2
通讯作者：
Zhang DD
中科院分区：
文献类型：
--
作者：
Jiang T;Chen N;Zhao F;Wang XJ;Kong B;Zheng W;Zhang DD
II型子宫内膜癌是多种女性生殖器恶性肿瘤中恶性程度最高、复发率最高的恶性肿瘤，主要表现为浆液性透明细胞型。转录因子Nrf2首次被描述为具有化学预防活性。Nrf2介导的细胞防御反应的激活通过上调一系列基因来保护细胞免受环境侮辱的毒性和致癌影响，这些基因可以解毒活性氧物种(ROS)并恢复细胞氧化还原动态平衡。然而，Nrf2的促癌作用最近被揭示出来。NRF2在几种类型的人类癌症组织和癌细胞系中呈结构性上调。此外，抑制Nrf2的表达使癌细胞对化疗药物敏感。本研究比较了不同类型子宫内膜肿瘤中Nrf2的组成水平。结果发现，Nrf2在子宫内膜浆液性癌(ESC)中高表达，而在复杂型增生(CH)和子宫内膜样癌(EEC)中无表达或边缘表达。同样，ESC来源的SPEC-2细胞株较EEC来源的Ishikawa细胞株具有更高的Nrf2表达水平，并且对顺铂和紫杉醇的毒性作用更具抵抗力。沉默Nrf2使SPEC-2细胞对化疗药物更敏感，而对Ishikawa细胞影响有限。使用细胞培养和SCID小鼠模型，通过过度表达Keap1敏化的SPEC-2细胞或SPEC-2来源的异种移植对化疗治疗的抑制Nrf2的表达。总而言之，我们为使用Nrf2抑制剂提高化疗药物的疗效和对抗化疗中的最大障碍--化疗耐药性提供了分子基础。
Type II endometrial cancer, which mainly presents as serous and clear cell types, has proved to be the most malignant and recurrent carcinoma among various female genital malignancies. The transcription factor, Nrf2, was first described as having chemopreventive activity. Activation of the Nrf2-mediated cellular defense response protects cells against the toxic and carcinogenic effects of environmental insults by upregulating an array of genes that detoxify reactive oxygen species (ROS) and restore cellular redox homeostasis. However, the cancer-promoting role of Nrf2 has recently been revealed. Nrf2 is constitutively upregulated in several types of human cancer tissues and cancer cell lines. Furthermore, inhibition of Nrf2 expression sensitizes cancer cells to chemotherapeutic drugs. In this study, the constitutive level of Nrf2 was compared in different types of human endometrial tumors. It was found that Nrf2 was highly expressed in endometrial serous carcinoma (ESC), whereas complex hyperplasia (CH) and endometrial endometrioid carcinoma (EEC) had no or marginal expression of Nrf2. Likewise, the ESC derived SPEC-2 cell line had a higher level of Nrf2 expression and was more resistant to the toxic effects of cisplatin and paclitaxel than that of the Ishikawa cell line, which was generated from EEC. Silencing of Nrf2 rendered SPEC-2 cells more susceptible to chemotherapeutic drugs while it had a limited effect on Ishikawa cells. Inhibition of Nrf2 expression by overexpressing Keap1 sensitized SPEC-2 cells or SPEC-2-derived xenografts to chemotherapeutic treatments using both cell culture and SCID mouse models. Collectively, we provide a molecular basis for the use of Nrf2 inhibitors to increase the efficacy of chemotherapeutic drugs and to combat chemoresistance, the biggest obstacle in chemotherapy.