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Review
. 2018 Apr 25;38(1):12.
doi: 10.1186/s40880-018-0288-x.

Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer

Pranavi Koppula  1   2 , Yilei Zhang  1 , Li Zhuang  1 , Boyi Gan  3   4   5
Affiliations
Review

Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer (VSports注册入口)

Pranavi Koppula et al. Cancer Commun (Lond). .

"VSports在线直播" Abstract

Cancer cells often upregulate nutrient transporters to fulfill their increased biosynthetic and bioenergetic needs, and to maintain redox homeostasis. One nutrient transporter frequently overexpressed in human cancers is the cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11; also known as xCT). SLC7A11 promotes cystine uptake and glutathione biosynthesis, resulting in protection from oxidative stress and ferroptotic cell death VSports手机版. Recent studies have unexpectedly revealed that SLC7A11 also plays critical roles in glutamine metabolism and regulates the glucose and glutamine dependency of cancer cells. This review discusses the roles of SLC7A11 in regulating the antioxidant response and nutrient dependency of cancer cells, explores our current understanding of SLC7A11 regulation in cancer metabolism, and highlights key open questions for future studies in this emerging research area. A deeper understanding of SLC7A11 in cancer metabolism may identify new therapeutic opportunities to target this important amino acid transporter for cancer treatment. .

Keywords: Cancer metabolism; Cystine; Ferroptosis; Glutamate; Nutrient dependency; Oxidative stress; SLC7A11; System x c −; xCT V体育安卓版. .

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Figures

Fig. 1
Fig. 1
Structure and transport function of system xc−. System xc− functions as a cystine/glutamate antiporter that imports one molecule of cystine in exchange for one molecule of intracellular glutamate. It is a heterodimer of the light chain subunit SLC7A11, which mediates transport activity of system xc−, and heavy chain subunit SLC3A2 that regulates trafficking of SLC7A11 to the plasma membrane
Fig. 2
Fig. 2
SLC7A11 promotes the oxidative stress response and inhibits ferroptosis. Extracellular cystine is imported into cells through SLC7A11 and converted to cysteine that in turn serves as the rate-limiting precursor for glutathione biosynthesis. Reduced glutathione (GSH) is used as a co-factor by various enzymes involved in ROS detoxification, such as GPX4. Overproduction of lipid hydroperoxides induces ferroptosis. GPX4 uses GSH to detoxify lipid hydroperoxides to lipid alcohols, thus repressing ferroptosis. γGCS γ-glutamylcysteine synthetase, GS glutathione synthetase, GPX4 glutathione peroxidase 4, GST glutathione S-transferase, GR glutathione reductase, Grx glutaredoxin, GSH reduced glutathione, GSSG oxidized glutathione, lipid-OOH lipid hydroperoxide, lipid-OH lipid alcohol Gly glycine
Fig. 3
Fig. 3
SLC7A11 regulates nutrient dependency of cancer cells. This schematic represents cells with high expression of SLC7A11. a Under normal conditions, SLC7A11 exports large amounts of intracellular glutamate in exchange for extracellular cystine. Cystine imported by SLC7A11 is converted to cysteine that supports glutathione biosynthesis and ROS detoxification. However, SLC7A11-mediated glutamate export limits intracellular glutamate supply to the TCA cycle and mitochondrial respiration, rendering such cells more dependent on glucose and/or glutamine supply for survival and growth. Glutamine is the major precursor for glutamate. Glucose provides the major carbon source for the TCA cycle as well as NADPH for glutathione biosynthesis and ROS detoxification. b Under glucose-deprived conditions, cells with high expression of SLC7A11 lack adequate supplies to maintain the TCA cycle and mitochondrial respiration. In addition, cystine imported by SLC7A11 depletes NAPDH and induces ROS under glucose deprivation conditions, possibly because cystine conversion to cysteine consumes NADPH, which is largely provided by glucose. These events result in enhanced cell death of SLC7A11-high cancer cells under glucose starvation. OXPHOS oxidative phosphorylation, PPP pentose phosphate pathway, GLS glutaminase, αKG α-ketoglutarate, Cys cysteine
Fig. 4
Fig. 4
SLC7A11 regulation by transcriptional, post-transcriptional, and post-translational mechanisms. Cellular stresses, such as oxidative stress and amino acid starvation, induce SLC7A11 transcription through NRF2 and/or ATF4 transcription factors, whereas p53 represses SLC7A11 expression. SLC7A11 mRNA stability can be negatively regulated by either microRNAs or NMD. Oxidative stress relieves NMD-mediated degradation of SLC7A11 mRNA. mTORC2 phosphorylates SLC7A11 at serine 26, resulting in inhibition of SLC7A11 transport activity. NMD nonsense-mediated mRNA decay
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