NF-κB/Lipocalin 2 Signaling Pathway Mitigates the Chemoresistance of BRAFV600E-Mutant Colorectal Cancer to Cisplatin by Promoting Ferroptosis
TL;DR
A key role is found for NF-κB/Lipocalin 2 (LCN2)-signaling-pathway-induced ferroptosis in modulating cisplatin sensitivity of V600E-overexpressing CRC cells to cisplatin within a KRAS-mutant cellular background, implying LCN2 as a potential therapeutic target.
Abstract
Simple Summary Colorectal cancer (CRC) driven by the BRAFV600E (V600E) mutation represents one of the most clinically challenging subtypes of the disease, characterized by rapid progression and a striking resistance to conventional chemotherapy. Despite its poor prognosis, the molecular mechanisms have remained unclarified. In this study, we found a key role for NF-κB/Lipocalin 2 (LCN2)-signaling-pathway-induced ferroptosis in modulating cisplatin sensitivity of V600E-overexpressing CRC cells to cisplatin within a KRAS-mutant cellular background. The results show that V600E overexpression cells exhibit suppressed NF-κB/LCN2 activation and insensitivity to cisplatin treatment. The NF-κB/LCN2 signaling could induce ferroptosis through increasing the accumulation of iron, leading to activation of the Fenton reaction and increasing ROS levels. Restoring LCN2 expression in V600E overexpression cells could partially attenuate the inhibition of ferroptosis and chemoresistance of cisplatin. Interestingly, we further found an unexpected interplay between ferroptosis and apoptosis, which is also regulated by LCN2. Taken together, these findings imply LCN2 as a potential therapeutic target. Aiming the crosstalk between ferroptosis and apoptosis may offer a potential strategy to overcome chemotherapy resistance of this high-risk CRC subtype.