RRC ID 62874
著者 Kim DH, Kim WD, Kim SK, Moon DH, Lee SJ.
タイトル TGF-β1-mediated repression of SLC7A11 drives vulnerability to GPX4 inhibition in hepatocellular carcinoma cells.
ジャーナル Cell Death Dis
Abstract System xc- contributes to glutathione (GSH) synthesis and protects cells against ferroptosis by importing cystine and exchanging it with glutamate. Transforming growth factor β1 (TGF-β1) induces redox imbalance; however, its role in system xc- regulation remains poorly understood. The present study was the first to show that TGF-β1 repressed the protein and mRNA levels of xCT, a catalytic subunit of system xc-, in PLC/PRF/5, Huh7, Huh6, and HepG2 cells with an early TGF-β1 gene signature but not in SNU387, SNU449, SNU475, and SK-Hep1 cells with a late TGF-β1 gene signature. TGF-β1 treatment for 24 h reduced xCT expression in a dose-dependent manner but this TGF-β1-induced repression was blunted by pretreatment with a TGF-β1 receptor inhibitor. TGF-β1-mediated xCT repression was prevented by Smad3, but not Smad2 or Smad4, knockdown, whereas it was enhanced by Smad3 overexpression. TGF-β1 decreased GSH levels in control cells but not xCT-overexpressed cells. Furthermore, TGF-β1 increased reactive oxygen species (ROS) levels in PLC/PRF/5 cells and enhanced tert-butyl hydroperoxide-induced ROS levels in Huh7 cells; these changes were reversed by xCT overexpression. TGF-β1 treatment ultimately induced the ferrostatin-1- and deferoxamine-dependent lipid peroxidation after 2 days and 8 days in PLC/PRF/5 and Huh7 cells but not in SNU475 and SK-Hep1 cells. Pre-treatment of TGF-β1 for 2 days enhanced the reduction of cell viability induced by RSL3, a GSH peroxidase 4 (GPX4) inhibitor, in PLC/PRF/5 and Huh7 cells. In conclusion, TGF-β1 represses xCT expression via Smad3 activation and enhances lipid peroxidation in hepatocellular carcinoma cells with an early TGF-β1 signature, which would benefit from the targeting of GPX4.
巻・号 11(5)
ページ 406
公開日 2020-5-29
DOI 10.1038/s41419-020-2618-6
PII 10.1038/s41419-020-2618-6
PMID 32471991
PMC PMC7260246
MeSH Amino Acid Transport System y+ / metabolism* Carcinoma, Hepatocellular / genetics* Carcinoma, Hepatocellular / pathology Cell Line, Tumor Gene Expression Regulation, Neoplastic / drug effects Glutathione / metabolism Humans Lipid Peroxidation / drug effects Liver Neoplasms / genetics* Liver Neoplasms / pathology Peroxides / pharmacology Phospholipid Hydroperoxide Glutathione Peroxidase / antagonists & inhibitors* Phospholipid Hydroperoxide Glutathione Peroxidase / metabolism Reactive Oxygen Species / metabolism Receptors, Transforming Growth Factor beta / metabolism Signal Transduction / drug effects Smad3 Protein / metabolism Time Factors Transforming Growth Factor beta1 / metabolism*
IF 6.304
リソース情報
ヒト・動物細胞 HuH-6(RCB1367) Hep G2(RCB1886)