Lipid second messengers, particularly those derived from the
polyphosphoinositide metabolism, play a pivotal role in multiple cell signaling networks.
Phosphoinositide 3-kinase (PI3K) generate 3'-phosphorylated
inositol lipids that are key players in a multitude of cell functions. One of the best characterized targets of PI3K
lipid products is the
serine/threonine protein kinase Akt (
protein kinase B, PKB). Recent findings have implicated the PI3K/Akt pathway in
tumorigenesis because it stimulates cell proliferation and suppresses apoptosis. However, it was thought that this signal transduction network would exert its carcinogenetic effects mainly by operating in the cytoplasm. Evidence accumulated over the past 15 years has highlighted the presence of an autonomous nuclear
inositol lipid cycle, and strongly suggests that
lipid molecules are important components of signaling pathways operating at the nuclear level. PI3K, its
lipid product
phosphatidylinositol (3,4,5) trisphosphate (
PtdIns(3,4,5)P3), and Akt have been identified within the nucleus and recent data suggest that they counteract apoptosis also by operating in this cell compartment through a block of
caspase-activated DNase and inhibition of
chromatin condensation. In this review, we shall summarize the most updated and intriguing findings about nuclear PI3K/
PtdIns(3,4,5)P3/Akt in relationship with
tumorigenesis and suppression of apoptotic stimuli.