INFORMAZIONI SU
CHAOUDHARY Himanshi
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Supervisore: Prof. Xodo Modulation of gene expression in ras-mutant cancers by small-molecule ligands targeting critical DNA or RNA G-rich regions |
| More than 90 % of patients with PDAC carry KRAS-activating mutations. Despite the KRAS dependence of PDAC, the inhibition of MAPK and KRAS has proven to have limited therapeutic efficacy. Therefore, alternative strategies have been explored. Given the KRAS-dependence of NRF2, we recently focused on the inhibition of the KRAS-NRF2 axis. By CRISPR-Cas9 we knockout NRF2 in mutant KRAS G12D PDAC cells. Long-term deletion of NRF2 induces a metabolic reprogramming of Panc-1 cells, which become unresponsive to glucose deprivation but rely on arginine catabolism. Rescue experiments demonstrate the direct role of NRF2 in controlling arginine catabolism. NRF2-depleted cells become dependent on iNOS for NO generation and maintenance of invasive properties, while they rely on CKB for ATP generation. On the contrary, glucose restriction impacts on the malignancy of wt PANC-1 cells but not on NRF2 KO cells. Mechanistically, the strong suppression of peptidyl arginine deaminases (PADI) observed in NRF2 ko cells limits demethylation of arginine to citrulline and nearly blunts citrullination. We hypothesize that the loss of NRF2-dependent citrullination of key metabolic enzymes could be responsible for the metabolic reprogramming observed in NRF2 KO cells. In summary, our study demonstrates a critical role of NRF2 in controlling cellular metabolism, highlighting the existence of metabolic short-circuits that allow cancer cells to adapt to non-permissive metabolic conditions. | |