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, Huei Lee

Research output: Contribution to journalArticle

41 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)41692-41705
Number of pages14
JournalOncotarget
Volume6
Issue number39
DOIs
Publication statusPublished - 2015

Fingerprint

Non-Small Cell Lung Carcinoma
Cisplatin
Messenger RNA
Up-Regulation
bcl-2 Genes
Drug Therapy
Heme Oxygenase-1
Chromatin Immunoprecipitation
Multiple Drug Resistance
Luciferases
Real-Time Polymerase Chain Reaction
Transcription Factors
Antioxidants
Binding Sites
Regression Analysis
Enzymes
Pharmaceutical Preparations
Genes
Neoplasms

Keywords

  • Cisplatin sensitivity
  • Lung cancer
  • Nrf2
  • P53

ASJC Scopus subject areas

  • Oncology

Cite this

Tung, M. C., Lin, P. L., Wang, Y. C., He, T. Y., Lee, M. C., Yeh, S. D., ... Lee, H. (2015). Mutant p53 confers chemoresistance in non-small cell lung cancer by upregulating Nrf2. Oncotarget, 6(39), 41692-41705. https://doi.org/10.18632/oncotarget.6150

Mutant p53 confers chemoresistance in non-small cell lung cancer by upregulating Nrf2. / Tung, Min Che; Lin, Po Lin; Wang, Yao Chen; He, Tsung Ying; Lee, Ming Ching; Yeh, Sauh Der; Chen, Chih Yi; Lee, Huei.

In: Oncotarget, Vol. 6, No. 39, 2015, p. 41692-41705.

Research output: Contribution to journalArticle

Tung, MC, Lin, PL, Wang, YC, He, TY, Lee, MC, Yeh, SD, Chen, CY & Lee, H 2015, 'Mutant p53 confers chemoresistance in non-small cell lung cancer by upregulating Nrf2', Oncotarget, vol. 6, no. 39, pp. 41692-41705. https://doi.org/10.18632/oncotarget.6150
Tung, Min Che ; Lin, Po Lin ; Wang, Yao Chen ; He, Tsung Ying ; Lee, Ming Ching ; Yeh, Sauh Der ; Chen, Chih Yi ; Lee, Huei. / Mutant p53 confers chemoresistance in non-small cell lung cancer by upregulating Nrf2. In: Oncotarget. 2015 ; Vol. 6, No. 39. pp. 41692-41705.
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