Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85724, USA.
Cancer Res. 2010 Jul 1;70(13):5486-96. doi: 10.1158/0008-5472.CAN-10-0713. Epub 2010 Jun 8.
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 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 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 the Ishikawa cell line, which was generated from EEC. Silencing of Nrf2 rendered SPEC-2 cells more susceptible to chemotherapeutic drugs, whereas 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 severe combined immunodeficient 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.
Ⅱ型子宫内膜癌主要表现为浆液性和透明细胞型，已被证明是女性生殖系统各种恶性肿瘤中最具恶性和复发性的癌种。转录因子 Nrf2 最初被描述为具有化学预防作用。激活 Nrf2 介导的细胞防御反应通过上调一系列基因来解毒活性氧并恢复细胞氧化还原稳态，从而保护细胞免受环境刺激物的毒性和致癌作用。然而，最近揭示了 Nrf2 的致癌作用。几种类型的人类癌症组织和癌细胞系中 Nrf2 持续上调。此外，抑制 Nrf2 表达可使癌细胞对化疗药物敏感。在这项研究中，比较了不同类型的人子宫内膜肿瘤中 Nrf2 的组成性水平。结果发现，Nrf2 在子宫内膜浆液性癌（ESC）中高表达，而复杂增生和子宫内膜子宫内膜样癌（EEC）中 Nrf2 无表达或低表达。同样，ESC 衍生的 SPEC-2 细胞系具有更高水平的 Nrf2 表达，并且对顺铂和紫杉醇的毒性作用比源自 EEC 的 Ishikawa 细胞系更具抗性。沉默 Nrf2 使 SPEC-2 细胞对化疗药物更敏感，而对 Ishikawa 细胞的影响有限。通过过表达 Keap1 抑制 Nrf2 表达可使 SPEC-2 细胞或 SPEC-2 衍生的异种移植物对使用细胞培养和严重联合免疫缺陷小鼠模型的化疗治疗更敏感。总的来说，我们为使用 Nrf2 抑制剂来提高化疗药物的疗效并对抗化疗中最大的障碍——化疗耐药性提供了分子基础。
