Protein synthesis inhibition by flavonoids: Roles of eukaryotic initiationfactor 2 alpha kinases

Flavonoids such as genistein and quercetin suppress tumor cell growth in vi tro and in vivo. Many metabolic enzymes, including protein kinases, are kno wn to be inhibited by flavonoids, yet the molecular targets and biochemical mechanisms of the tumor growth suppression remain unclear. Here, we find t hat flavonoids inhibit protein synthesis in both mouse and human leukemia c ells. This inhibition is associated with phosphorylation of the alpha-subun it of eukaryotic initiation factor 2 (eIF2 alpha), a key regulatory mechani sm of protein translation. Three mammalian eIF2 alpha kinases have been ide ntified: the interferon-inducible double-stranded RNA-dependent kinase (PKR ), the heme-regulated inhibitor (HRI), and the very recently discovered PER K/PEK. We find that all of these eIF2 alpha kinases can be activated by que rcetin and genistein, indicating redundant roles of the eIF2 alpha kinases. Thus, activation of eIF2 alpha kinases appears to be a mechanism by which flavonoids can inhibit the growth of tumor and leukemia cells. (C) 1999 Aca demic Press.