Molecular control of arsenite-induced apoptosis in Caenorhabditis elegans: Roles of insulin-like growth factor-1 signaling pathway

Apoptosis is one of the main cellular processes in responses to arsenic, the well known environmental carcinogen. By using the nematode Caenorhabditis elegans as an in vivo model, we found that insulin-like growth factor-1 networks and their target protein DAF-16/FOXO, known as key regulators of energy metabolism and growth, played important roles in arsenite-induced apoptosis. Inactivation of DAF-2, AGE-1 and AKT-1 caused worms more susceptible to arsenite-induced apoptosis, which could be attenuated by DAF-16 knockout. Worms with inactivated AKT-2 and SGK-1 or with constitutively activated PDK-1 and AKT-1 showed low levels of apoptosis, which could be elevated by DAF-16 mutation. Our results demonstrated that DAF-2/IGF-1R, AGE-1/PI3K, PDK-1/PDK1 and AKT-1/PKB negatively regulated the arsenite-induced apoptosis, whereas AKT-2 and SGK-1 acted proapoptotically. DAF-16/FOXO antagonized IGF-1 signals in signaling the arsenite-induced apoptosis, and apoptosis promoted by DAF-16 inactivation was attributed to its higher sensitivity to oxidative stress.