Loss of function mutations in the Nrf2 inhibitor, Kelch-like ECH-associated protein (Keap1), results in constitutive activation of Nrf2 function in non-small cell lung cancer.
In this study, we show that RNAi-mediated lowering of Nrf2 levels in non-small-cell lung cancer (NSCLC) cell lines (A549 and H460) led to a dramatic increase in endogenous reactive oxygen species (ROS) levels.
Nrf2, a redox-sensing transcription factor, on constitutive activation in non-small-cell lung cancer cells upregulates a wide spectrum of genes involved in redox balance, glutathione metabolism, and drug detoxification, which contribute to chemoresistance and tumorigenicity.
In addition, we found a statistically significant correlation between the presence of Keap1/Nrf2 mutations and increased MRP3 messenger RNA levels in our NSCLC patient samples.
In non-small-cell lung cancer (NSCLC) cell lines and NSCLC patients, Keap1 is often present as a biallelic mutant that results in constitutive activation of Nrf2 function, which contributes to cytoprotection against oxidative stress and xenobiotics.
Unexpectedly, stable knockdown of KEAP1 by lentiviral shRNA sensitized three independent NSCLC cell lines (A549, HTB-178, and HTB-182) to multiple chemotherapeutic agents, including arsenic trioxide (As(2)O(3)), etoposide, and doxorubicin, despite moderately increased NRF2 levels.
Here we show that Nrf2-mediated NSCLC cell proliferation is dually regulated by epidermal growth factor receptor (EGFR) signaling and an Nrf2 repressor protein Keap1 (Kelch-like ECH-associated protein-1).
In this study, the increased copy number of the NRF2 gene was analyzed by real-time polymerase chain reaction (real-time-PCR) amplifications in 90 surgically-treated non-small cell lung cancer (NSCLC) cases.
Unexpectedly, stable knockdown of KEAP1 by lentiviral shRNA sensitized three independent NSCLC cell lines (A549, HTB-178, and HTB-182) to multiple chemotherapeutic agents, including arsenic trioxide (As(2)O(3)), etoposide, and doxorubicin, despite moderately increased NRF2 levels.
Samples of human non-small cell lung cancer (NSCLC) were used to correlate MOF with clinicopathological parameters and NF-E2-related factor 2 (Nrf2) downstream genes.
Here we show that the activity of this pathway is highly heterogeneous and is regulated by NRF2, a transcription factor frequently deregulated in NSCLC.
Collectively, mutant p53 may confer cisplatin resistance via upregulation of Nrf2 expression, and Nrf2 mRNA level may predict chemotherapeutic response and outcomes in NSCLC.
Thus, a substantial fraction of human NSCLCs activates an NRF2-dependent transcriptional program that regulates serine and glycine metabolism and is linked to clinical aggressiveness.