Glutathione and xCT: Chemoresistance in Tumor Cells

Glutathione, called GSH in its reduced form and GSSG or L(-)-Glutathione in its oxidized form, is an endogenous antioxidant found in most cells in the body. Glutathione's functions include detoxifying xenobiotics from the body, assisting in membrane transport, facilitating regulation of nitrogen via the nitric oxide cycle, and playing a functional role in the metabolism of iron.  Glutathione is maintained within the cell by a heterodimeric cystine/glutamate exchanger system, which exchanges intracellular glutamate for extracellular cystine.  SLC7A11 (also called xCT) and SLC3A2 (also called CD98) are the two proteins responsible for maintaining intracellular glutathione as well as non-vesicular glutamate release.

In cancer research, glutathione and xCT have been shown to have a pivotal role in chemo drug resistance.  Glutathione’s detoxification properties are useful in ridding the body of harmful toxins as well as contributing to chemoresistance in tumor cells.  It has been shown that increased expression of the xCT gene decreases the functionality certain chemo drugs by increasing glutathione levels in the cell.  Alternatively, when xCT inhibitors are used, the potency of these drugs is increased.   Celestrol an anticancer drug; specifically targeting gliomas, is one of these chemo drugs shown to be susceptible to glutathione chemoresistance.

Furthermore, research into gastrointestinal tumor growth showed that CD44v, a variant adhesion molecule that is expressed in cancer stem-like cells, interacts with xCT to control the intracellular level of reduced glutathione (GSH).  As the expression of CD44v is increased, the level of reduced glutathione is also increased.  This results in an increase in the cellular defense of reactive oxygen species (ROS) and tumor growth.  When the CD44 protein is removed, there is a loss of xCT from the cell surface and tumor growth is suppressed.

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