1. Academic Validation
  2. IFNγ-mediated repression of system xc- drives vulnerability to induced ferroptosis in hepatocellular carcinoma cells

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

  • J Leukoc Biol. 2021 Aug;110(2):301-314. doi: 10.1002/JLB.3MA1220-815RRR.
Rui Kong 1 Nan Wang 1 Wei Han 1 Wen Bao 1 Jie Lu 1
Affiliations

Affiliation

  • 1 Department of Gastroenterology, Shanghai Tenth People's Hospital Affiliated to Tongji University, Tongji University, School of Medicine, Shanghai, China.
Abstract

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.

Keywords

IFNγ; JAK/STAT pathway; cell ferroptosis; system xc−.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15534
    99.0%, 线粒体膜电位探针