[논문]TGF-β1-mediated repression of SLC7A11 drives vulnerability to GPX4 inhibition in hepatocellular carcinoma cells

Kim, Do Hyung; Kim, Won Dong; Kim, Sang Kyum; Moon, Dae Hyuk; Lee, Seung Jin

doi:10.1038/s41419-020-2618-6

[해외논문] TGF-β1-mediated repression of SLC7A11 drives vulnerability to GPX4 inhibition in hepatocellular carcinoma cells 원문보기

Cell death & disease, v.11 no.5, 2020년, pp.406 -

Kim, Do Hyung (College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134 Republic of Korea) , Kim, Won Dong (Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505 Republic of Korea) , Kim, Sang Kyum (College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134 Republic of Korea) , Moon, Dae Hyuk (Department of Nuclear Medicine, Asan Medical Center, University of Ulsan, College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505 Republic of Korea) , Lee, Seung Jin (College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134 Republic of Korea)

Abstract ▼ AI-Helper

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.

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