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Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
Modification of platinum sensitivity by KEAP1/NRF2 signals in non-small cell lung cancer
Yijun Tian1, Kongming Wu1, Qian Liu1
1Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.
Background:
The objective of this study was to evaluate the effect of platinum-based drugs on nuclear-factor erythroid2 like 2 (NRF2) signaling in non-small cell lung cancer cell lines with or without Kelch-like ECH-associated protein 1 (KEAP1) mutations and to determine the role of NRF2 and KEAP1 on platinum-based drug treatment.
Methods:
We used real-time PCR to assess relative mRNA expression and used western blotting and immunofluorescence assays to assess protein expression. Small interfering RNA and shuttle plasmids were used to modulate the expression of NRF2, wild-type KEAP1, and mutant KEAP1. Drug sensitivity to platinum-based drugs was evaluated with Cell Count Kit-8.
Results:
We found that platinum-based therapies modified the NRF2 signaling pathway differently in KEAP1-mutated non-small cell lung cancer (NSCLC) cell lines compared with wild-type KEAP1 cell lines. The reactive degree of NRF2 signaling also varies between nedaplatin and cisplatin. The modification of NRF2 or KEAP1 expression in NSCLC cell lines disrupted downstream gene expression and cell sensitivity to platinum-based drugs. Finally, gene expression data retrieved from The Cancer Genome Atlas (TCGA) consortium indicated that KEAP1 mutation significantly affects NRF2 signaling activity in patients with NSCLC.
Conclusions:
Our findings suggest that NRF2 signaling plays an indispensable role in NSCLC cell sensitivity to platinum-based treatments and provides a rationale for using NRF2 as a specific biomarker for predicting which patients will be most likely to benefit from platinum-based treatment.
Insights
Platinum-based drugs affect nuclear-factor erythroid2-like 2 (NRF2) signaling differently in non-small cell lung cancer cells with or without Kelch-like ECH-associated protein 1 (KEAP1) mutations. NRF2 signaling is crucial for predicting patient response to these treatments.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Non-small cell lung cancer (NSCLC) is a major cause of cancer mortality.
- Platinum-based drugs are a cornerstone of NSCLC treatment.
- The role of nuclear-factor erythroid2-like 2 (NRF2) and Kelch-like ECH-associated protein 1 (KEAP1) in platinum resistance is not fully understood.
Purpose of the Study:
- To investigate the impact of platinum-based drugs on NRF2 signaling in NSCLC cell lines with varying KEAP1 mutation statuses.
- To elucidate the role of NRF2 and KEAP1 in mediating sensitivity to platinum-based chemotherapy in NSCLC.
Main Methods:
- Real-time PCR for mRNA expression analysis.
- Western blotting and immunofluorescence for protein expression.
- RNA interference and plasmid transfection to modulate NRF2 and KEAP1 levels.
- Cell Count Kit-8 assay for drug sensitivity evaluation.
Main Results:
- Platinum-based therapies differentially modulated NRF2 signaling in KEAP1-mutated versus wild-type NSCLC cell lines.
- The response of NRF2 signaling varied between cisplatin and nedaplatin.
- Altering NRF2 or KEAP1 expression significantly impacted downstream gene expression and drug sensitivity.
- KEAP1 mutations were found to significantly influence NRF2 signaling activity in NSCLC patients (TCGA data).
Conclusions:
- NRF2 signaling is essential for NSCLC cell sensitivity to platinum-based treatments.
- NRF2 can serve as a predictive biomarker for identifying NSCLC patients likely to respond to platinum-based therapy.
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