Home > In process > Lipocalin-2 regulates the expression of interferon-stimulated genes and the susceptibility of prostate cancer cells to oncolytic virus infection. > print

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024 7 _ |a 10.1016/j.ejcb.2023.151328
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024 7 _ |a 0171-9335
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024 7 _ |a 1618-1298
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037 _ _ |a DKFZ-2025-02450
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Barer, Lilach
|b 0
245 _ _ |a Lipocalin-2 regulates the expression of interferon-stimulated genes and the susceptibility of prostate cancer cells to oncolytic virus infection.
260 _ _ |a München
|c 2023
|b Elsevier
336 7 _ |a article
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520 _ _ |a 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.
588 _ _ |a Dataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de
650 _ 7 |a Antiviral response
|2 Other
650 _ 7 |a EHDV-TAU
|2 Other
650 _ 7 |a Interferons
|2 Other
650 _ 7 |a Lipocalin-2
|2 Other
650 _ 7 |a Oncolytic virotherapy
|2 Other
650 _ 7 |a Prostate cancer
|2 Other
650 _ 7 |a Interferons
|0 9008-11-1
|2 NLM Chemicals
650 _ 7 |a Janus Kinases
|0 EC 2.7.10.2
|2 NLM Chemicals
650 _ 7 |a Lipocalin-2
|2 NLM Chemicals
650 _ 7 |a STAT Transcription Factors
|2 NLM Chemicals
650 _ 7 |a LCN2 protein, human
|2 NLM Chemicals
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Interferons: genetics
|2 MeSH
650 _ 2 |a Interferons: metabolism
|2 MeSH
650 _ 2 |a Janus Kinases: metabolism
|2 MeSH
650 _ 2 |a Lipocalin-2: genetics
|2 MeSH
650 _ 2 |a Lipocalin-2: metabolism
|2 MeSH
650 _ 2 |a Oncolytic Viruses: genetics
|2 MeSH
650 _ 2 |a Oncolytic Viruses: metabolism
|2 MeSH
650 _ 2 |a Prostatic Neoplasms: genetics
|2 MeSH
650 _ 2 |a Prostatic Neoplasms: therapy
|2 MeSH
650 _ 2 |a Prostatic Neoplasms: pathology
|2 MeSH
650 _ 2 |a Signal Transduction: physiology
|2 MeSH
650 _ 2 |a STAT Transcription Factors: metabolism
|2 MeSH
650 _ 2 |a Virus Diseases
|2 MeSH
700 1 _ |a Schröder, Sarah K
|b 1
700 1 _ |a Weiskirchen, Ralf
|b 2
700 1 _ |a Bacharach, Eran
|b 3
700 1 _ |a Ehrlich, Marcelo
|b 4
773 _ _ |a 10.1016/j.ejcb.2023.151328
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