Metformin is believed to exert its antitumor effects via multiple mechanisms (right panel in Figure 2), including activation of AMPK and inhibition of mTOR (13, 97, 98), reduction of blood glucose (21), reduction of insulin and IGF-1(98), inhibition of cancer stem cells (99), modulation of adenosine A1 receptor (100), down-regulating drug-resistant gene P-glycoprotein (P-gp) (94), inhibition of midkine (101), and induction of apoptosis (102, 103). Here, PRKAA2 is linked to cancer.