Why PGD₂ has different functions from PGE₂

Prostaglandin (PG) D₂ and PGE₂ are positional isomers; however, they sometimes exhibit opposite physiological functions, such as in cancer development. Because DP receptors are considered to be a duplicated copy of EP2 receptors, PGD₂ and PGE₂ cross-react with both receptors. These prostanoids may act as biased agonists for each receptor. In reviewing this field, a hypothesis was proposed to explain the opposed effects of these prostanoids from the viewpoints of the evolution of, mutations in, and biased activities of their receptors. Previous findings showing more mutations/variations in DP receptors than EP2 receptors among individuals worldwide indicate that DP receptors are still in a rapid evolutionary stage. The opposing effects of these prostanoids on cancer development may be attributed to the biased activity of PGE₂ for DP receptors, which may incidentally develop during the process of the old ligand, PGE₂ gaining selectivity to newly diverged DP receptors.