SLC27A5 Promotes Sorafenib-induced Ferroptosis in Hepatocellular Carcinoma by Downregulating Glutathione Reductase

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2023 Jan 12

PMID 36635256

Authors

Feng-Li Xu

Xiao-Hong Wu

Chang Chen

Kai Wang

Lu-Yi Huang

Jie Xia

Yi Liu

Xue-Feng Shan

Ni Tang

Affiliations

Soon will be listed here.

Abstract

Sorafenib, a first-line drug for advanced hepatocellular carcinoma (HCC), shows a favorable anti-tumor effect while resistance is a barrier impeding patients from benefiting from it. Thus, more efforts are needed to lift this restriction. Herein, we first find that solute carrier family 27 member 5 (SLC27A5/FATP5), an enzyme involved in the metabolism of fatty acid and bile acid, is downregulated in sorafenib-resistant HCC. SLC27A5 deficiency facilitates the resistance towards sorafenib in HCC cells, which is mediated by suppressing ferroptosis. Further mechanism studies reveal that the loss of SLC27A5 enhances the glutathione reductase (GSR) expression in a nuclear factor erythroid 2-related factor 2 (NRF2)-dependent manner, which maintains glutathione (GSH) homeostasis and renders insensitive to sorafenib-induced ferroptosis. Notably, SLC27A5 negatively correlates with GSR, and genetic or pharmacological inhibition of GSR strengthens the efficacy of sorafenib through GSH depletion and the accumulation of lipid peroxide products in SLC27A5-knockout and sorafenib-resistant HCC cells. Based on our results, the combination of sorafenib and carmustine (BCNU), a selective inhibitor of GSR, remarkably hamper tumor growth by enhancing ferroptotic cell death in vivo. In conclusion, we describe that SLC27A5 serves as a suppressor in sorafenib resistance and promotes sorafenib-triggered ferroptosis via restraining the NRF2/GSR pathway in HCC, providing a potential therapeutic strategy for overcoming sorafenib resistance.

Citing Articles

Glutathione reductase underlies the stability of mutant p53 by antagonizing protein glutathionylation.

Wang L, Zhong S, Fan X, Xu Y, Wang M, Xu Y Redox Biol. 2025; 81:103522.

PMID: 39983342 PMC: 11893312. DOI: 10.1016/j.redox.2025.103522.

The impact of solute carrier proteins on disrupting substance regulation in metabolic disorders: insights and clinical applications.

Du J, Shen M, Chen J, Yan H, Xu Z, Yang X Front Pharmacol. 2025; 15():1510080.

PMID: 39850557 PMC: 11754210. DOI: 10.3389/fphar.2024.1510080.

Ferroptosis, a therapeutic target for cardiovascular diseases, neurodegenerative diseases and cancer.

Li Y, Liu C, Fang B, Chen X, Wang K, Xin H J Transl Med. 2024; 22(1):1137.

PMID: 39710702 PMC: 11663363. DOI: 10.1186/s12967-024-05881-6.

Identification of key genes to predict response to chemoradiotherapy and prognosis in esophageal squamous cell carcinoma.

Cui Y, Wen J, Fu J, Leng C Front Mol Biosci. 2024; 11:1512715.

PMID: 39633985 PMC: 11614722. DOI: 10.3389/fmolb.2024.1512715.

Targeting STK26 and ATG4B: miR-22-3p as a modulator of autophagy and tumor progression in HCC.

Li K, Bai Y, Wang J, Ren L, Mo A, Liu R Transl Oncol. 2024; 51:102214.

PMID: 39608212 PMC: 11635773. DOI: 10.1016/j.tranon.2024.102214.

References

Yan X, Zhang X, Wang L, Zhang R, Pu X, Wu S . Inhibition of Thioredoxin/Thioredoxin Reductase Induces Synthetic Lethality in Lung Cancers with Compromised Glutathione Homeostasis. Cancer Res. 2018; 79(1):125-132. PMC: 7293542. DOI: 10.1158/0008-5472.CAN-18-1938. View

Zhang C, Liu Z, Bunker E, Ramirez A, Lee S, Peng Y . Sorafenib targets the mitochondrial electron transport chain complexes and ATP synthase to activate the PINK1-Parkin pathway and modulate cellular drug response. J Biol Chem. 2017; 292(36):15105-15120. PMC: 5592685. DOI: 10.1074/jbc.M117.783175. View

Lachaier E, Louandre C, Godin C, Saidak Z, Baert M, Diouf M . Sorafenib induces ferroptosis in human cancer cell lines originating from different solid tumors. Anticancer Res. 2014; 34(11):6417-22. View

Zhu Z, Du S, Du Y, Ren J, Ying G, Yan Z . Glutathione reductase mediates drug resistance in glioblastoma cells by regulating redox homeostasis. J Neurochem. 2017; 144(1):93-104. DOI: 10.1111/jnc.14250. View

Siegel R, Miller K, Fuchs H, Jemal A . Cancer Statistics, 2021. CA Cancer J Clin. 2021; 71(1):7-33. DOI: 10.3322/caac.21654. View

Xia Y, Wang G, Jiang M, Liu X, Zhao Y, Song Y . A Novel Biological Activity of the STAT3 Inhibitor Stattic in Inhibiting Glutathione Reductase and Suppressing the Tumorigenicity of Human Cervical Cancer Cells via a ROS-Dependent Pathway. Onco Targets Ther. 2021; 14:4047-4060. PMC: 8275107. DOI: 10.2147/OTT.S313507. View

Muri J, Thut H, Bornkamm G, Kopf M . B1 and Marginal Zone B Cells but Not Follicular B2 Cells Require Gpx4 to Prevent Lipid Peroxidation and Ferroptosis. Cell Rep. 2019; 29(9):2731-2744.e4. DOI: 10.1016/j.celrep.2019.10.070. View

Yao F, Deng Y, Zhao Y, Mei Y, Zhang Y, Liu X . A targetable LIFR-NF-κB-LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis. Nat Commun. 2021; 12(1):7333. PMC: 8683481. DOI: 10.1038/s41467-021-27452-9. View

Zhang F, Xue M, Jiang X, Yu H, Qiu Y, Yu J . Identifying SLC27A5 as a potential prognostic marker of hepatocellular carcinoma by weighted gene co-expression network analysis and in vitro assays. Cancer Cell Int. 2021; 21(1):174. PMC: 7968262. DOI: 10.1186/s12935-021-01871-6. View

10.

Wang M, Wang N, Zhang H, Sun L, Xu Q, Liang L . Fatty acid transport protein-5 (FATP5) deficiency enhances hepatocellular carcinoma progression and metastasis by reprogramming cellular energy metabolism and regulating the AMPK-mTOR signaling pathway. Oncogenesis. 2021; 10(11):74. PMC: 8589992. DOI: 10.1038/s41389-021-00364-5. View

11.

Hubbard B, Doege H, Punreddy S, Wu H, Huang X, Kaushik V . Mice deleted for fatty acid transport protein 5 have defective bile acid conjugation and are protected from obesity. Gastroenterology. 2006; 130(4):1259-69. DOI: 10.1053/j.gastro.2006.02.012. View

12.

Shimizu S, Takehara T, Hikita H, Kodama T, Tsunematsu H, Miyagi T . Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma. Int J Cancer. 2011; 131(3):548-57. DOI: 10.1002/ijc.26374. View

13.

Rojo de la Vega M, Chapman E, Zhang D . NRF2 and the Hallmarks of Cancer. Cancer Cell. 2018; 34(1):21-43. PMC: 6039250. DOI: 10.1016/j.ccell.2018.03.022. View

14.

Cheng A, Kang Y, Chen Z, Tsao C, Qin S, Kim J . Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2008; 10(1):25-34. DOI: 10.1016/S1470-2045(08)70285-7. View

15.

Tang F, Gao R, Jeevan-Raj B, Wyss C, Kalathur R, Piscuoglio S . LATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function. Nat Commun. 2019; 10(1):5755. PMC: 6917744. DOI: 10.1038/s41467-019-13591-7. View

16.

Zou Y, Li H, Graham E, Deik A, Eaton J, Wang W . Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis. Nat Chem Biol. 2020; 16(3):302-309. PMC: 7353921. DOI: 10.1038/s41589-020-0472-6. View

17.

Doll S, Proneth B, Tyurina Y, Panzilius E, Kobayashi S, Ingold I . ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2016; 13(1):91-98. PMC: 5610546. DOI: 10.1038/nchembio.2239. View

18.

Pohl J, Ring A, Hermann T, Stremmel W . Role of FATP in parenchymal cell fatty acid uptake. Biochim Biophys Acta. 2004; 1686(1-2):1-6. DOI: 10.1016/j.bbalip.2004.06.004. View

19.

Louandre C, Ezzoukhry Z, Godin C, Barbare J, Maziere J, Chauffert B . Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib. Int J Cancer. 2013; 133(7):1732-42. DOI: 10.1002/ijc.28159. View

20.

Zhao L, Zhou X, Xie F, Zhang L, Yan H, Huang J . Ferroptosis in cancer and cancer immunotherapy. Cancer Commun (Lond). 2022; 42(2):88-116. PMC: 8822596. DOI: 10.1002/cac2.12250. View