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

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. 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.

Inhibiting xCT/SLC7A11 induces ferroptosis of myofibroblastic hepatic stellate cells and protects against liver fibrosis

“…Cell culture studies Primary HSCs were isolated from healthy [12][13][14][15][16] week old C57BL/6 mice. HSCs were cultured for up to 7 days in Gibco® DMEM containing 10% fetal bovine serum, and 1% penicillin-streptomycin (Life Technologies, Grand Island, NY) to induce activation.…”

“…xCT plays critical roles in GSH biosynthesis, ROS defense, glucose and glutamine consumption, mitochondrial respiration, lipid metabolism, metabolic reprogramming and cell growth in various cancer cell lines and animal models of cancer. 13 Like cancer cells, other types of highly proliferating cells express xCT, and xCT -/fibroblasts failed to survive under conventional culture conditions due to an insufficient uptake of cystine. 14 Pharmaceutical inhibitors of xCT, erastin or sulfasalazine (SASP), 5 were also used to evaluate the role of xCT in human MF-HSCs.…”

“…xCT mediated-cystine uptake supports GSH biosynthesis and protects cells from oxidative stress and ferroptotic cell death. 13 Therefore, we hypothesized that xCT inhibition induces ferroptosis in MF-HSCs. In support of this hypothesis, we found that erastin caused dramatic cell death, as indicated by the direct measurement of the DNA debris released into the culture medium (Fig.…”

Low-protein/high-carbohydrate diet induces AMPK-dependent canonical and non-canonical thermogenic response in subcutaneous adipose tissue

“…Interestingly, AAR promoted an increase of cystine transporter Slc7a11 (Fig. 6B), which is implicated in the maintenance of the intracellular thiol pool (Koppula et al, 2018), indicating an attempt of adipocytes to preserve redox homeostasis. Notably, NAC addition inhibited such event ( Fig.…”

Single cell atlas of domestic pig brain illuminates the conservation and divergence of cell types at spatial and species levels

“…Transporter genes SLC1A2 and SLC7A11 expression in C11 (AST). SLC1A2 has been known essential for excitatory neurotransmitter glutamate clear [67] and SLC7A11 mainly functions in cysteine and glutamate transport systems [68] (FigureS2c). In addition, we found some CD markers that have a specific expression pattern in C4 (EX), C8 (IN), C10 (EX), C11 (AST), such as CDH2, CD47, and IGF1R (Table S7).…”