Figure 1. GPxs and COX/LOX activity.

Mitochondria and NADPH oxidases (NOX) are intracellular sources of H₂O₂ or other hydroperoxides (ROOH). H₂O₂ and ROOH are reduced by all GPx1, 2, and 4 and also by GPx3. Hydroperoxides activate COX-2, which in principle, is inhibited by all GPxs, preferentially; however, by GPx4. COX-2 forms PGE2, which in an autocrine loop can induce the expression of COX-2 to further increase PGE2 production to promote cancer cell proliferation, invasion, self-renewal, and differentiation of CSCs.