Aldo-keto reductases are biomarkers of NRF2 activity and are co-ordinately overexpressed in non-small cell lung cancer

Abstract

Background:Although the nuclear factor-erythroid 2-related factor 2 (NRF2) pathway is one of the most frequently dysregulated in cancer, it is not clear whether mutational status is a good predictor of NRF2 activity. Here we utilise four members of the aldo-keto reductase (AKR) superfamily as biomarkers to address this question.Methods:Twenty-three cell lines of diverse origin and NRF2-pathway mutational status were used to determine the relationship between AKR expression and NRF2 activity. AKR expression was evaluated in lung cancer biopsies and Cancer Genome Atlas (TCGA) and Oncomine data sets.Results:AKRs were expressed at a high basal level in cell lines carrying mutations in the NRF2 pathway. In non-mutant cell lines, co-ordinate induction of AKRs was consistently observed following activation of NRF2. Immunohistochemical analysis of lung tumour biopsies and interrogation of TCGA data revealed that AKRs are enriched in both squamous cell carcinomas (SCCs) and adenocarcinomas that contain somatic alterations in the NRF2 pathway but, in the case of SCC, AKRs were also enriched in most other tumours.Conclusions:An AKR biomarker panel can be used to determine NRF2 status in tumours. Hyperactivation of the NRF2 pathway is far more prevalent in lung SCC than previously predicted by genomic analyses.

Resistance to gefitinib and cross‐resistance to irreversible EGFR‐TKIs mediated by disruption of the Keap1‐Nrf2 pathway in human lung cancer cells

“…Upon exposure to oxidative or electrophilic stress, Nrf2 is released from Keap1, allowing it to evade the ubiquitination process and translocate from the cytoplasm to the nucleus in order to transcriptionally activate ARE-containing genes such as AKRs, HO1, NQO1, GCLC, and GCLM, which encode metabolic and cytoprotective enzymes (19,32,38,41,42) in normal, healthy cells. In contrast to its cytoprotective role in normal cells, accumulating evidence suggests that high, persistent activation of Nrf2, along with its downstream target genes such as AKR1C1, AKR1C3, and HO1, is associated with progression, metastasis, and resistance against chemoand radiotherapy in various types of cancers, including NSCLC, as a poor prognostic factor (21,24,43). The Keap1-Nrf2 pathway is therefore considered to be a new oncogenic signaling pathway and an attractive target for the development of therapeutics to treat cancer.…”

NRF2-regulated metabolic gene signature as a prognostic biomarker in non-small cell lung cancer

“…In addition, the KEAP1 mutant gene signature (27 genes) of Goldstein et al [ 38 ] also contains a set of overlapping downregulated genes present in our combinatorial analysis of data from both microarrays: ABCC2, CABYR, CYP4F11, NR0B1, and PGD ( Supplementary Table 5 ). It is noteworthy that a recent publication on a lung cancer biomarker specific to the aldo-keto reductase (AKR) family of proteins states that one of these proteins identified in our NRMGS – AKR1C1 – can be used as a potential biomarker in lung cancer [ 39 ]. It is well known that the classic NRF2-regulated gene GCLC (glutamate-cysteine ligase catalytic subunit) is highly expressed in lung cancer and increased GCLC expression is highly correlated with poorer survival.…”

Extreme heterogeneity of influenza virus infection in single cells

“…Table delineating genes in Figure 9 that are associated with the response to oxidative stress ( Duong et al, 2017 ; Jung et al, 2017 ; Lee and Ryu, 2017 ; Peuchant et al, 2006 ; MacLeod et al, 2016 ; Jiang et al, 2016 ; Gorrini et al, 2013 ; Miura et al, 2013 ; Kim et al, 2006 ; Banning et al, 2005 ; Murray et al, 2003 ; Doyle et al, 1999 ).…”