Loss of Lipocalin2 confers cisplatin vulnerability through modulating NF-ĸB mediated ferroptosis via ferroportin

Cisplatin is a widely used anti-cancer drug. Unfortunately, many cancers often develop resistance, which contributes to tumor recurrence and poorly prognosis. Growing knowledge has suggested the therapeutic potential of Ferroptosis in Cancer. Lipocalin2 (LCN2) is demonstrated to be a critical iron metabolic factor and implies in Ferroptosis. Here, we aim to explore its role in chemotherapy resistance. The influence of LCN2 on colorectal Cancer (CRC) cell chemoresistance and Ferroptosis were evaluated by in vitro and in vivo approaches. The interaction between LCN2, NF-ĸB and Ferroportin (FPN) was assessed by western blots, immunohistochemistry and dual luciferase reporter assays. Results showed that LCN2 was highly expressed in tumor regression grade 1 (TRG1) cases than that in TRG3 specimens. Loss of LCN2 contributed to resistance to cisplatin-induced Ferroptosis. Mechanistically, loss of LCN2 inhibited cisplatin sensitivity and cisplatin-induced Ferroptosis through elevating FPN expression which was regulated by NF-ĸB, subsequently reducing Fe²⁺ mediated Fenton reaction. Furthermore, FPN expression rate was much lower in TRG1 cases, and negative correlation between LCN2 and FPN expression was observed in clinical specimens. Collectively, low LCN2 expression enhances insensitivity of cisplatin to CRC cells via Fenton reaction mediated Ferroptosis. LCN2/NF-ĸB/FPN pathway might be potentially utilized for chemoresistance strategy. LCN2 and FPN expression might be a promising biomarker of chemotherapy effect for CRC patients.

Chemoresistance; Lipocalin2; biomarkers; colorectal cancer; ferroptosis.