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Review
. 2022 Feb;23(2):47.
doi: 10.3892/ol.2021.13165. Epub 2021 Dec 14.

Research progress on SLC7A11 in the regulation of cystine/cysteine metabolism in tumors

Xiang Tang  1 , Wei Chen  2 , Hui Liu  2 , Na Liu  1 , Deyu Chen  1 , Dalong Tian  2 , Jingzhi Wang  2
Affiliations
Review

"V体育安卓版" Research progress on SLC7A11 in the regulation of cystine/cysteine metabolism in tumors

Xiang Tang et al. Oncol Lett. 2022 Feb.

Abstract

Solute carrier family 7 member 11 (SLC7A11) is a major transporter regulating cysteine metabolism and is widely expressed in a variety of tumor cells. SLC7A11 plays an important role in the occurrence, development, invasion and metastasis of tumors by regulating the transport of cysteine in the tumor microenvironment. SLC7A11 is expected to become a new therapeutic target and prognostic indicator for the individualized treatment of patients. According to relevant research reports, SLC7A11 can predict the stages and metastasis of liver, breast and lung cancer. Therefore, an in-depth exploration of the role of SLC7A11 in tumors may be important for the screening, early diagnosis, treatment and prognosis of patients with tumors. The current review summarizes the research progress on SLC7A11 in liver cancer, lung cancer and other tumors on the basis of previous primary studies. In addition, the present review systematically elaborates on the three main aspects of SLC7A11 pathways in some tumors, the cancer-promoting mechanisms, and the therapeutic relationship between SLC7A11 and tumors. Finally, the present review aims to provide a reference for assessing whether SLC7A11 can be used as a prognostic indicator and treatment target for tumor patients, and the future research direction with regard to SLC7A11 in tumors. VSports手机版.

Keywords: cysteine; ferroptosis; solute carrier family 7 member 11; tumor V体育安卓版. .

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Conflict of interest statement

The authors declare that they have no competing interests.

V体育平台登录 - Figures

Figure 1.
Figure 1.
Structure and function of Xc-. The Xc- system consists of two subunits, namely, light (SLC7A11) and heavy (SLC3A2) chain subunits. SLC7A11 exerts the main biological function and transport activity, whereas SLC3A2 only participates in maintaining the stability of SLC7A11 as a chaperone protein. SLC7A11 transfers a molecule of extracellular cystine into the cell while transferring a molecule of intracellular glutamate out of the cell. The cystine transported into the cell is quickly reduced to cysteine. Next, cysteine and glutamic acid are combined under the action of GCL to form γ-glutamyl cysteine, and glycine is added to the C-terminus of γ-Glu-Cys through GS to produce reduced GSH. GPX4 then reduces lipid hydroperoxides into lipid alcohols through GSH, thereby inhibiting ferroptosis. At this time, GSH is oxidized into GSSG, which can be reduced to GSH again through GR. GCL, glutamate cysteine ligase; GS, glutathione synthetase; GPX4, glutathione peroxidase 4; GR, glutathione reductase; GSH, reduced glutathione; GSSG, oxidized glutathione; L-OOH, lipid hydroperoxide; L-OH, lipid alcohol; ROS, reactive oxygen species; SLC7A11, solute carrier family 7 member 11; SLC3A2, solute carrier family 3 member 2.
Figure 2.
Figure 2.
SLC7A11 is regulated by transcriptional, post-transcriptional and post-translational mechanisms. Under stress conditions, such as oxidative stress and amino acid deficiency, the GCN2-eIF2α and KEAP1-NRF2 signal axes can induce SLC7A11 transcription, and the SWI/SNF chromatin remodeling complex can further promote the NRF2-mediated transcriptional activation of SLC7A11. However, p53 and ATF3 inhibit the expression of SLC7A11 under basal conditions. In epigenetics, the methylation of H3K4 can activate the transcription of SLC7A11, whereas the methylation of H3K9me3 and H3K27me3 can inhibit the transcription activity of SLC7A11. BRD4 can inhibit the transcription of SLC7A11 by regulating histone acetylation. The stability of SLC7A11 mRNA can be regulated by microRNA. miR-139-5p, mir-27a, and mir-375 can destroy the stability of SLC7A11 mRNA and inhibit its transcription. mTORC2 can regulate the phosphorylation of SLC7A11 at serine site 26 and inhibit the transport activity of SLC7A11 directly or through the AKT signaling pathway. CD44v and OTUB1 can inhibit the degradation of SLC7A11, thereby stabilizing the SLC7A11 protein and improving its transport activity. GCN2, general control nonderepressible 2; eIF2α, eukaryotic initiation factor 2α; KEAP1, kelch-like ECH-associated protein 1; NRF2, nuclear erythroid 2-related factor 2; mTORC2, mammalian target of rapamycin complex 2; OTUB1, OTU deubiquitinase ubiquitin aldehyde binding 1; ATF, activating transcription factor; p53, tumor protein 53; SWI/SNF, switch/sucrose non-fermentable modeling complex; BRD4, bromodomain-containing protein 4; miR, microRNA; CD44v, CD44 variant; SLC7A11, solute carrier family 7 member 11; SLC3A2, solute carrier family 3 member 2.
Figure 3.
Figure 3.
Signal pathways regulating the transcriptional activity of SLC7A11. Lung cancer in patients is often accompanied by mutations in the KRAS gene, and mutant KRAS acts on NRF2 by activating its downstream pathways (including the classic MAPK, PI3K/AKT and RAL pathways) to promote the transcriptional activity of SLC7A11. In addition, in patients with estrogen receptor-positive breast cancer, breast cancer cells can upregulate the transcriptional activity of SLC7A11 through the IGF-I/IRS-1/PI3K signaling axis. NRF2, nuclear erythroid 2-related factor 2; ER, estrogen receptor; SLC7A11, solute carrier family 7 member 11; RAL, RAS-related protein.
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