Fig. 5

Function of CD44 in promoting resistance to oxidative stress with metabolic reprogramming. Alternative splicing of the CD44 gene results in the generation of multiple protein isoforms. CD44 standard isoform (CD44s) binds to PKM2, thereby promoting aerobic glycolysis in cancer cells (Warburg effect) and the pentose phosphate pathway (PPP). The PPP provides enough NADPH to convert oxidative form of glutathione (GSSG) to reduced form of glutathione (GSH) [147, 152]. On the other hand, CD44 variant isoform (CD44v) is overexpressed in epithelial cancer stem cells (CSCs), and its colocalization with the xCT subunit of system Xc(–), a glutamate/cystine antiporter, promotes the uptake of cystine and the consequent synthesis of the antioxidant GSH, which reduces the amount of reactive oxygen species (ROS) [117, 119, 147]. The red region of CD44v indicates the variable exons 8-10 which are inserted by ESRP1-induced alternative splicing