For the critical role of cancer stem/initiating cells in tumorigenesis and cancer development, researchers explored whether metformin affects cancer initiating cells, and found that metformin (1 mM) activates hexaribonucleotide-binding protein 3(FOX3) via AMPK activation, which is sufficient to promote the differentiation of glioma-initiating cells into nontumorigenic cells [71]. This evidence concerns the gene PRKAA1 and central nervous system cancer.