Mutant p53 confers chemoresistance in non-small cell lung cancer by upregulating Nrf2.
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.
Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Surgery, Tungs' Taichung MetroHarbor Hospital, Taichung, Taiwan.
Min-Che
MC
Tung
Institute of Medicine, Department of Surgery, Chung Shan Medical University, Taichung, Taiwan.
Po-Lin
PL
Lin
Division of Chest Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan.
Yao-Chen
YC
Wang
Institute of Medicine, Department of Surgery, Chung Shan Medical University, Taichung, Taiwan.
Tsung-Ying
TY
He
Department of Thoracic Surgery, Taichung Veteran General Hospital, Taichung, Taiwan.
Ming-Ching
MC
Lee
Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.
Sauh D
SD
Yeh
Division of Thoracic Surgery, Department of Surgery, Chung Shan Medical University, Taichung, Taiwan.
Chih-Yi
CY
Chen
Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
Huei
H
Lee
D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001665:Binding Sites; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014162:Transfection; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; C494811:BCL2L1 protein, human; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D002945:Cisplatin
Nrf2; cisplatin sensitivity; lung cancer; p53