Systematic identification of a nuclear receptor-enriched predictive signature for erastin-induced ferroptosis
| Autor: | Hyuk-Jin Cha, Yun Jeong Kim, Eun-Woo Lee, Jeong Yoon Choi, Haeseung Lee, Wankyu Kim, Hyeon Joon Kong, Eun Ji Kwon, Ok Seon Kwon |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cell type Programmed cell death Redox imbalance Clinical Biochemistry Receptors Cytoplasmic and Nuclear Biochemistry Piperazines NRF2 Transcriptome Drug sensitivity prediction 03 medical and health sciences 0302 clinical medicine Drug response biomarker medicine Humans Ferroptosis Gene Transcription factor lcsh:QH301-705.5 Aryl hydrocarbon receptor lcsh:R5-920 Oncogene biology Erastin Organic Chemistry Elastic net Cancer medicine.disease Glutathione 030104 developmental biology Nuclear receptor lcsh:Biology (General) Cell culture Pharmacogenomics Cancer cell biology.protein Cancer research lcsh:Medicine (General) 030217 neurology & neurosurgery Research Paper |
| Zdroj: | Redox Biology, Vol 37, Iss, Pp 101719-(2020) Redox Biology |
| ISSN: | 2213-2317 |
| Popis: | Erastin, which has been initially identified as a synthetic lethal compound against cancer expressing an RAS oncogene, inhibits cystine/glutamate antiporters and causes ferroptic cell death in various cell types, including therapy-resistant mesenchymal cancer cells. However, despite recent emerging evidence for the mechanisms underlying ferroptosis, molecular biomarkers associated with erastin-dependent ferroptosis have not yet been identified. In the present study, we employed isogenic lung cancer cell models with therapy-resistant mesenchymal properties to show that a redox imbalance leads to glutathione depletion and ferroptotic cell death. Subsequent gene expression analysis of pan-cancer cell lines revealed that the activity of transcription factors, including nuclear factor erythroid 2-related factor 2 (NRF2) and aryl hydrocarbon receptor (AhR), serve as important markers of erastin resistance. Based on the integrated expression of genes in the nuclear receptor meta-pathway (NRM), we constructed an NRM model and validated its robustness using an independent pharmacogenomics dataset. The NRM model was further evaluated by employing it in the sensitivity testing of nine cancer cell lines for which erastin sensitivities had not yet been undetermined. Our pharmacogenomics approach has the potential to pave the way for the efficient classification of patients for therapeutic intervention using erastin or erastin analogs. |
| Databáze: | OpenAIRE |
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