There are two opposing sides to the controversial cysteine/glutamate antiporter. On one hand, it can be viewed a guardian of the cell, protecting it from the damaging oxidative stress that can cause cell death and even cancer. But, conversely, it has a dark side, actually facilitating cancer in a number of ways.
The cystine/glutamate antiporter, system xc–, transports cystine into the cell and glutamate out of the cell in a 1:1 ratio. It is composed of two subunits: xCT (also known as SLC7A11) is responsible for the substrate specificity and transport activity, and CD98 (also called 4F2hc or SLC3A2) is involved in directing the heterodimer to the plasma membrane.
Cysteine is required not only for protein biosynthesis, but most significantly is the rate-limiting precursor in the biosynthesis of the tripeptide thiol glutathione (GSH), an antioxidant that is vital in defending cells against cytotoxic reactive oxygen species (ROS). For example, one study showed that, although not required in steady-state conditions, the absence of xCT (in mutant mice) led to impaired survival of activated macrophages subjected to oxidative stress at sites of inflammation, leading to chronic inflammation and inflammation-induced carcinogenesis.
IHC analysis of xCT in the absorptive epithelia of human intestinal villi tissue
xCT is constitutively expressed in the brain, and it has been argued that this reflects defence against the high levels of ROS that brain cells are subjected to. However, other studies suggest that xCT knock-out mice do not experience a reduction in GSH levels or increased oxidative stress in the brain. There is also debate concerning the release by system xc– of glutamate, a prominent neurotransmitter. xCT mutant mice have been shown to have memory defects, demonstrating a positive role of xCT, but glutamate efflux by system xc– can also be damaging, as excessive glutamate causes cell death by excitotoxicity.
The latter is just one of the ways system xc– has been reported to promote cancer, in this case as a method used by gliomas to kill surrounding cells to make space to grow. In addition, system xc– provides cysteine to cancers that cannot synthesize it (e.g. leukemias and lymphomas); aids drug resistance via the generation of GSH, which assists in the detoxification of drugs via multidrug resistance proteins; and xCT has even been discovered to mediate the fusion and entry of KSHV, the virus that causes Kaposi’s sarcoma.
There is still much to be learned about this contradictory transporter, and many studies are looking into drugs targeting xCT to treat various diseases.
- PMID: 21409388
- PMID: 20308543
- PMID: 21490221
- PMID: 18181196
Novus Biologicals offers xCT reagents for your research needs including:
Written by Carly Hammond