A positive role of phosphatidylinositol 3-kinase in aging phenotype expression in cultured human diploid fibroblasts

In order to detect the role that phosphatidylinositol 3-kinase (PI3K) plays in the aging of human diploid fibroblasts, we analyzed cellular inositol phospholipids and expression of PI3Ks. In aged cells a decrease in phosphatidylinositol 3,4-bisphosphate (PI3,4P2) was notable, while phosphatidylinositol 3-phosphate (PI3P) and phosphatidylinositol 4,5-bisphosphate (PI4,5P2) decreased slightly. On the other hand, the messages of PI3K IIα, Vps34, and p110δ decreased and that of PI3K IIβ increased during aging. These changes might relate to the aging phenomena, with the PI3K subspecies functioning differentially. Consistently, a PI3K inhibitor LY294002 greatly suppressed enlargement and flattening of cell body and nucleus as well as cell proliferation, both phenotypes being typical of aged cells. An oxidative stress, pulse exposure to hydrogen peroxide (H2O2), induced these senescent cell-like phenotypes, which LY294002 was also able to abolish. Upon examining three different cell systems (HL-60, N1E-115, and PC-12 cells) we found clear parallelism in a cellular event between the dependence on a PI3K activity and the sensitivity to H2O2. On the analogy of these relationships, we could hypothesize that expression of an aging phenotype such as the morphogenesis is positively promoted by some PI3K subspecies, if such a phenotype as cell cycling is negatively affected by attenuation of another PI3K function in the course of cellular aging. [Copyright &y& Elsevier]