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Gain of NRF2 function in Non small cell lung cancer promotes tumorigenecity and confers therapeutic resistance
Author(s) -
Biswal Shyam,
Singh Anju
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1136.11
Subject(s) - small hairpin rna , cancer research , a549 cell , in vivo , cell growth , lung cancer , cancer cell , transfection , cell culture , cancer , drug resistance , growth inhibition , pharmacology , medicine , biology , oncology , biochemistry , gene knockdown , microbiology and biotechnology , genetics
Rationale: Loss of function mutations in the Nuclear factor erythroid‐2 related factor‐2 (NRF2) inhibitor, Kelch‐like ECH‐associated protein (KEAP1), in non‐small‐cell lung cancer (NSCLC) results in gain of NRF2 function. This study was designed to investigate the dysregulated NRF2‐KEAP1 pathway as a novel determinant of tumorigenecity and therapeutic resistance. Methods: Global gene expression profiling of A549 cells transfected with siRNA. Generation of A549 and H460 cells stably expressing NRF2 shRNA to (a) to evaluate drug cytotoxicity using cell viability assays. (b) growth of these cells using in vitro and in vivo assays. Results: siRNA mediated lowering of NRF2 levels in NSCLC (A549 and H460) cell lines results in global decrease in cellular thiol levels and the drug efflux proteins involved in counteracting electrophiles and detoxification of a broad spectrum of drugs. Cancer cells expressing NRF2 shRNA demonstrated enhanced drug accumulation and sensitivity to commonly used chemotherapeutic drugs. NRF2 shRNA abrogated neoplastic cellular proliferation in vitro and in vivo. These results demonstrate that gain of NRF2 function in NSCLC cells plays an important role in promoting tumor growth and confers resistance against drug induced cell death. Conclusion: Targeting NRF2 activity in lung cancer could be a promising strategy suppress tumor growth and circumvent therapeutic resistance.