TY  - JOUR
A1  - Meier, Julia
A1  - Schnetz, Matthias
A1  - Beck, Susanne
A1  - Schmid, Tobias
A1  - Dominguez, Monica
A1  - Kalinovic, Sanela
A1  - Daiber, Andreas
A1  - Brüne, Bernhard
A1  - Jung, Michaela
T1  - Iron-bound lipocalin-2 protects renal cell carcinoma from ferroptosis
T2  - Metabolites
N2  - 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.
KW  - lipocalin-2
KW  - iron
KW  - ROS
KW  - SLC7A11
KW  - Nrf2
KW  - ISR
KW  - p-eIF2α
KW  - erastin
KW  - ferroptosis
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/61332
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-613321
SN  - 2218-1989
VL  - 11
IS  - 5, art. 329
SP  - 1
EP  - 21
PB  - MDPI
CY  - Basel
ER  -