Iron-bound lipocalin-2 protects renal cell carcinoma from ferroptosis

  • 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.
Author:Julia Meier, Matthias Schnetz, Susanne Beck, Tobias SchmidORCiDGND, Monica Dominguez, Sanela KalinovicORCiD, Andreas DaiberORCiDGND, Bernhard BrüneORCiD, Michaela JungORCiD
Parent Title (English):Metabolites
Place of publication:Basel
Document Type:Article
Date of Publication (online):2021/05/19
Date of first Publication:2021/05/19
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2021/06/30
Tag:ISR; Nrf2; ROS; SLC7A11; erastin; ferroptosis; iron; lipocalin-2; p-eIF2α
Issue:5, art. 329
Page Number:21
First Page:1
Last Page:21
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0