Although dietary antioxidant supplementation or activation of endogenous antioxidants by NRF2 reduces oxidative stress and promotes early lung tumor progression, little is known about its effect on lung cancer metastasis.
Mutations in KEAP1/NFE2L2 genes always cause persistent Nrf2 activation in lung cancer cells that confer therapeutic resistance and aggressive tumorigenic activity, dictating either poor prognosis or short duration of response to chemotherapy in clinical observations.
Our data demonstrate that KEAP1/NRF2-mutant lung cancer is a microenvironmentally distinct, biologically heterogeneous, and clinically underestimated disease.
An in vivo study in mice xenotransplanted with A549 cells to further explore the therapeutic potential of K-563 revealed that it also inhibited Keap1/Nrf2 pathway in lung cancer tumors.
We propose that Nrf2 activates a metastatic program by inhibiting the heme- and Fbxo22-mediated degradation of Bach1, and that Ho1 inhibitors represent an effective therapeutic strategy to prevent lung cancer metastasis.
<i>KEAP1</i> silencing by promoter methylation is widely reported in solid tumors as part of the complex regulation of the KEAP1/NRF2 axis, but its prognostic role remains to be addressed in lung cancer.
They found that lico A significantly promoted the tumor-suppressor miR-144-3p expression, so as to up-regulate ER stress-response protein CHOP (CCAAT/-enhancer-binding protein homologous protein) by down-regulating nuclear factor E2-related factor 2 (Nrf2), finally inducing apoptotic cell death in lung cancer.
Importantly, potential avenues and implications for therapeutic targeting of KEAP1-NRF2 pathway vulnerabilities for lung cancer patients will be highlighted.
Intriguingly, the signalling molecules perturbed by CCRK are divergent and cancer-specific, including the cell cycle regulators CDK2, cyclin D1, cyclin E and RB in glioblastoma, ovarian carcinoma and colorectal cancer, and KEAP1-NRF2 cytoprotective pathway in lung cancer.