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• W3163440004 endingPage "329" @default.
• W3163440004 startingPage "329" @default.
• W3163440004 abstract "While the importance of the iron-load of lipocalin-2 (Lcn-2) in promoting tumor progression is widely appreciated, underlying molecular mechanisms largely remain elusive. Considering its role as an iron-transporter, we aimed at clarifying iron-loaded, holo-Lcn-2 (hLcn-2)-dependent signaling pathways in affecting renal cancer cell viability. Applying RNA sequencing analysis in renal CAKI1 tumor cells to explore highly upregulated molecular signatures in response to hLcn-2, we identified a cluster of genes (SLC7A11, GCLM, GLS), which are implicated in regulating ferroptosis. Indeed, hLcn-2-stimulated cells are protected from erastin-induced ferroptosis. We also noticed a rapid increase in reactive oxygen species (ROS) with subsequent activation of the antioxidant Nrf2 pathway. However, knocking down Nrf2 by siRNA was not sufficient to induce erastin-dependent ferroptotic cell death in hLcn-2-stimulated tumor cells. In contrast, preventing oxidative stress through N-acetyl-l-cysteine (NAC) supplementation was still able to induce erastin-dependent ferroptotic cell death in hLcn-2-stimulated tumor cells. Besides an oxidative stress response, we noticed activation of the integrated stress response (ISR), shown by enhanced phosphorylation of eIF-2α and induction of ATF4 after hLcn-2 addition. ATF4 knockdown as well as inhibition of the ISR sensitized hLcn-2-treated renal tumor cells to ferroptosis, thus linking the ISR to pro-tumor characteristics of hLcn-2. Our study provides mechanistic details to better understand tumor pro-survival pathways initiated by iron-loaded Lcn-2." @default.
• W3163440004 created "2021-05-24" @default.
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• W3163440004 date "2021-05-19" @default.
• W3163440004 modified "2023-10-06" @default.
• W3163440004 title "Iron-Bound Lipocalin-2 Protects Renal Cell Carcinoma from Ferroptosis" @default.
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• W3163440004 doi "https://doi.org/10.3390/metabo11050329" @default.
• W3163440004 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/8161288" @default.
• W3163440004 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34069743" @default.
• W3163440004 hasPublicationYear "2021" @default.
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