High Levels of Nrf2 Determine Chemoresistance in Type II Endometrial Cancer

被引:239
作者
Jiang, Tao [1 ]
Chen, Ning [2 ,5 ]
Zhao, Fei [1 ]
Wang, Xiao-Jun [1 ]
Kong, Beihua [5 ]
Zheng, Wenxin [2 ,3 ,4 ]
Zhang, Donna D. [1 ,4 ]
机构
[1] Univ Arizona, Coll Pharm, Dept Pharmacol & Toxicol, Tucson, AZ 85721 USA
[2] Univ Arizona, Coll Med, Dept Pathol, Tucson, AZ 85724 USA
[3] Univ Arizona, Coll Med, Dept Obstet & Gynecol, Tucson, AZ 85724 USA
[4] Univ Arizona, Coll Med, Arizona Canc Ctr, Tucson, AZ 85724 USA
[5] Shandong Univ, Qilu Hosp, Dept Obstet & Gynecol, Jinan 250100, Peoples R China
关键词
ENHANCES SUSCEPTIBILITY; ADAPTIVE RESPONSE; SIGNALING PATHWAY; LUNG-CANCER; KEAP1; CARCINOMA; MICE; CARCINOGENESIS; RESISTANCE; MUTATIONS;
D O I
10.1158/0008-5472.CAN-10-0713
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
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. Cancer Res; 70(13); 5486-96. (C)2010 AACR.
引用
收藏
页码:5486 / 5496
页数:11
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