IFNγ‐mediated repression of system xc− drives vulnerability to induced ferroptosis in hepatocellular carcinoma cells

IFNγ released from CD8+ T cells or natural killer cells plays a crucial role in antitumor host immunity. Several studies have found that IFNγ is involved in regulating tumor cell proliferation and apoptosis. However, few studies have examined its role in cell ferroptosis. Here, we found that IFNγ tr...

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Published in:Journal of leukocyte biology Vol. 110; no. 2; pp. 301 - 314
Main Authors: Kong, Rui, Wang, Nan, Han, Wei, Bao, Wen, Lu, Jie
Format: Journal Article
Language:English
Published: Bethesda Oxford University Press 01.08.2021
Subjects:
Apoptosis
Cancer
Cancer therapies
CD8 antigen
Cell cycle
cell ferroptosis
Cell proliferation
Ferroptosis
G1 phase
Glutathione
Hepatocellular carcinoma
IFNγ
JAK/STAT pathway
Lipid peroxidation
Lipids
Liver cancer
Lymphocytes
Lymphocytes T
Membrane potential
mRNA
Natural killer cells
Peroxidation
Reactive oxygen species
system xc
Transforming growth factor-b1
Tumor cell lines
γ-Interferon
ISSN:0741-5400, 1938-3673, 1938-3673
Online Access:Get full text
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Summary:IFNγ released from CD8+ T cells or natural killer cells plays a crucial role in antitumor host immunity. Several studies have found that IFNγ is involved in regulating tumor cell proliferation and apoptosis. However, few studies have examined its role in cell ferroptosis. Here, we found that IFNγ treatment enhanced glutathione depletion, promoted cell cycle arrested in G0/G1 phase, increased lipid peroxidation, and sensitized cells to ferroptosis activators. Additionally, IFNγ down‐regulated the mRNA and protein levels of SLC3A2 and SLC7A11, two subunits of the glutamate‐cystine antiporter system xc− via activating the JAK/STAT pathway in hepatocellular carcinoma (HCC) cell lines. Furthermore, IFNγ increased reactive oxygen species levels and decreased mitochondiral membrane potential in Bel7402 and HepG2 cells. These changes were accompanied by decreased system xc− activity. Cancer cells exposed to TGFβ1 for 48 h showed sensitization to IFNγ + erastin‐induced ferroptosis, with decreased system xc− expression. In conclusion, IFNγ repressed system xc− activation via activating JAK/STAT signaling. Additionally, enhanced lipid peroxidation was associated with altered mitochondrial function in HCC cells. Our findings identified a role for IFNγ in sensitizing HCC cells to ferroptosis, which provided new insights for applying IFNγ as a cancer treatment. Graphical Shows IFN gamma is an effective modulator in inhibiting EMT‐associated growth of HCC via inducing ferroptosis, providing new insight into the use of IFN gamma for cancer treatment.
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ISSN:0741-5400
1938-3673
1938-3673
DOI:10.1002/JLB.3MA1220-815RRR