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.
Verfasserangaben: | Julia Meier, Matthias Schnetz, Susanne Beck, Tobias SchmidORCiDGND, Monica Dominguez, Sanela KalinovicORCiDGND, Andreas DaiberORCiDGND, Bernhard BrüneORCiD, Michaela JungORCiD |
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URN: | urn:nbn:de:hebis:30:3-613321 |
DOI: | https://doi.org/10.3390/metabo11050329 |
ISSN: | 2218-1989 |
Titel des übergeordneten Werkes (Englisch): | Metabolites |
Verlag: | MDPI |
Verlagsort: | Basel |
Dokumentart: | Wissenschaftlicher Artikel |
Sprache: | Englisch |
Datum der Veröffentlichung (online): | 19.05.2021 |
Datum der Erstveröffentlichung: | 19.05.2021 |
Veröffentlichende Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Datum der Freischaltung: | 30.06.2021 |
Freies Schlagwort / Tag: | ISR; Nrf2; ROS; SLC7A11; erastin; ferroptosis; iron; lipocalin-2; p-eIF2α |
Jahrgang: | 11 |
Ausgabe / Heft: | 5, art. 329 |
Seitenzahl: | 21 |
Erste Seite: | 1 |
Letzte Seite: | 21 |
HeBIS-PPN: | 482007249 |
Institute: | Medizin |
DDC-Klassifikation: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Sammlungen: | Universitätspublikationen |
Open-Access-Publikationsfonds: | Medizin |
Lizenz (Deutsch): | Creative Commons - Namensnennung 4.0 |