Oncotarget

Research Papers:

Mutant p53 confers chemoresistance in non-small cell lung cancer by upregulating Nrf2

Min-Che Tung, Po-Lin Lin, Yao-Chen Wang, Tsung-Ying He, Ming-Ching Lee, Sauh-Der Yeh, Chih-Yi Chen and Huei Lee _

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Oncotarget. 2015; 6:41692-41705. https://doi.org/10.18632/oncotarget.6150

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Abstract

Min-Che Tung1,3,*, Po-Lin Lin4,*, Yao-Chen Wang6, Tsung-Ying He4, Ming-Ching Lee7, Sauh-Der Yeh1, Chih-Yi Chen5 and Huei Lee2

1 Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan

2 Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan

3 Department of Surgery, Tungs’ Taichung MetroHarbor Hospital, Taichung, Taiwan

4 Institute of Medicine, Department of Surgery, Chung Shan Medical University, Taichung, Taiwan

5 Division of Thoracic Surgery, Department of Surgery, Chung Shan Medical University, Taichung, Taiwan

6 Division of Chest Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan

7 Department of Thoracic Surgery, Taichung Veteran General Hospital, Taichung, Taiwan

* These authors contributed equally to this work

Correspondence to:

Huei Lee, email:

Keywords: Nrf2, p53, cisplatin sensitivity, lung cancer

Received: July 20, 2015 Accepted: September 30, 2015 Published: October 19, 2015

Abstract

Nrf2 is a key transcription factor for genes coding for antioxidants, detoxification enzymes, and multiple drug resistance and it also confers resistance to anticancer drugs. Here, we hypothesized that mutant p53 could upregulate Nrf2 expression at the transcriptional level, thereby conferring cisplatin resistance in non-small cell lung cancer (NSCLC). Luciferase reporter assays and real-time PCR analysis indicated that the Nrf2 promoter activity and its mRNA levels were markedly suppressed by wild-type p53, but not by mutant p53. Chromatin immunoprecipitation (ChIP) further confirmed that wild-type p53 binds at the p53 putative binding site to block Sp1 binding to the Nrf2 promoter and consequently to suppress the Nrf2 promoter activity. The MTT assay indicated that an increase in Nrf2 expression by mutant p53 is responsible for cisplatin resistance. Among the Nrf2 downstream genes, Bcl-2 and Bcl-xL contribute more strongly to Nrf2-mediated cisplatin resistance when compared with heme oxygenase 1 (HO-1). Cox regression analysis showed that patients with high-Nrf2, high-Bcl-2, high-Bcl-xL mRNA tumors were more commonly occurred unfavorable response to cisplatin-based chemotherapy than their counterparts. The prognostic significance of Nrf2 mRNA levels on OS and RFS was also observed in patients who have received cisplatin-based chemotherapy, particularly in p53-mutant patients. Collectively, mutant p53 may confer cisplatin resistance via upregulation of Nrf2 expression, and Nrf2 mRNA level may predict chemotherapeutic response and outcomes in NSCLC.


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