TY  - JOUR
AU  - Barer, Lilach
AU  - Schröder, Sarah K
AU  - Weiskirchen, Ralf
AU  - Bacharach, Eran
AU  - Ehrlich, Marcelo
TI  - Lipocalin-2 regulates the expression of interferon-stimulated genes and the susceptibility of prostate cancer cells to oncolytic virus infection.
JO  - European journal of cell biology
VL  - 102
IS  - 2
SN  - 0171-9335
CY  - München
PB  - Elsevier
M1  - DKFZ-2025-02450
SP  - 151328
PY  - 2023
N1  - #DKFZ-MOST-Ca184#
AB  - Lipocalin-2 (LCN2) performs pleiotropic and tumor context-dependent functions in cancers of diverse etiologies. In prostate cancer (PCa) cells, LCN2 regulates distinct phenotypic features, including cytoskeleton organization and expression of inflammation mediators. Oncolytic virotherapy uses oncolytic viruses (OVs) to kill cancer cells and induce anti-tumor immunity. A main source of specificity of OVs towards tumor cells stems from cancer-induced defects in interferon (IFN)-based cell autonomous immune responses. However, the molecular underpinnings of such defects in PCa cells are only partially understood. Moreover, LCN2 effects on IFN responses of PCa cells and their susceptibility to OVs are unknown. To examine these issues, we queried gene expression databases for genes coexpressed with LCN2, revealing co-expression of IFN-stimulated genes (ISGs) and LCN2. Analysis of human PCa cells revealed correlated expression of LCN2 and subsets of IFNs and ISGs. CRISPR/Cas9-mediated stable knockout of LCN2 in PC3 cells or transient overexpression of LCN2 in LNCaP cells revealed LCN2-mediated regulation of IFNE (and IFNL1) expression, activation of JAK/STAT pathway, and expression of selected ISGs. Accordingly, and dependent on a functional JAK/STAT pathway, LCN2 reduced the susceptibility of PCa cells to infection with the IFN-sensitive OV, EHDV-TAU. In PC3 cells, LCN2 knockout increased phosphorylation of eukaryotic initiation factor 2α (p-eIF2α). Inhibition of PKR-like ER kinase (PERK) in PC3-LCN2-KO cells reduced p-eIF2α while increasing constitutive IFNE expression, phosphorylation of STAT1, and ISG expression; and decreasing EHDV-TAU infection. Together, these data propose that LCN2 regulates PCa susceptibility to OVs through attenuation of PERK activity and increased IFN and ISG expression.
KW  - Humans
KW  - Male
KW  - Interferons: genetics
KW  - Interferons: metabolism
KW  - Janus Kinases: metabolism
KW  - Lipocalin-2: genetics
KW  - Lipocalin-2: metabolism
KW  - Oncolytic Viruses: genetics
KW  - Oncolytic Viruses: metabolism
KW  - Prostatic Neoplasms: genetics
KW  - Prostatic Neoplasms: therapy
KW  - Prostatic Neoplasms: pathology
KW  - Signal Transduction: physiology
KW  - STAT Transcription Factors: metabolism
KW  - Virus Diseases
KW  - Antiviral response (Other)
KW  - EHDV-TAU (Other)
KW  - Interferons (Other)
KW  - Lipocalin-2 (Other)
KW  - Oncolytic virotherapy (Other)
KW  - Prostate cancer (Other)
KW  - Interferons (NLM Chemicals)
KW  - Janus Kinases (NLM Chemicals)
KW  - Lipocalin-2 (NLM Chemicals)
KW  - STAT Transcription Factors (NLM Chemicals)
KW  - LCN2 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:37321037
DO  - DOI:10.1016/j.ejcb.2023.151328
UR  - https://inrepo02.dkfz.de/record/306221
ER  -