Abstract
OBJECTIVES: The phosphatidylinositol 3-kinase (PI3-K)/Akt pathway is well known for the regulation of cell survival, proliferation, and some metabolic routes. MATERIALS AND METHODS: In this study, we document a novel role for the PI3-K/Akt pathway during cell death induced by apoptin, a tumour-selective inducer of apoptosis. RESULTS: We show for the first time that apoptin interacts with the p85 regulatory subunit, leading to constitutive activation of PI3-K. The inhibition of PI3-K activation either by chemical inhibitors or by genetic approaches severely impairs cell death induced by apoptin. Downstream of PI3-K, Akt is activated and translocated to the nucleus together with apoptin. Direct interaction between apoptin and Akt is documented. Co-expression of nuclear Akt significantly potentiates cell death induced by apoptin. Thus, apoptin-facilitated nuclear Akt, in contrast to when in its cytoplasmic pool, appears to be a positive regulator, rather than repressor of apoptosis. CONCLUSIONS: Our observations indicate that PI3-K/Akt pathways have a dual role in both survival and cell death processes depending on the stimulus. Nuclear Akt acts as apoptosis stimulator rather than as a repressor, as it likely gains access to a new set of substrates in the nucleus. The implicated link between survival and cell death pathways during apoptosis opens new pharmacological opportunities to modulate apoptosis in cancer, for example through the manipulation of Akt's cellular localization.