Molecular mechanisms of Akt mediated cellular proliferation and oncogenic transformation

The serine/threonine kinase Akt/PKB is a major downstream effector of growth factor mediated cellular survival. It is well known that Akt is frequently activated in a variety of human cancers and that hyperactivation of the PI3K/Akt pathway leads to increased proliferation and tumor formation. Therefore, determining the molecular mechanisms by which Akt promotes cellular proliferation and transformation will aid clinicians in developing novel therapeutic agents as well as combinatorial approaches to treating cancer.; Previous work has shown that activated Akt is sufficient to promote cell cycle progression and tumorigenesis. However, it has not been proven that Akt is required for these processes. Here, we provided genetic evidence that Akt is in-fact required for normal cell proliferation and susceptibility to oncogenic transformation in vitro independently of its anti-apoptotic activity, functional p53, or functional FOXO, yet is mTORC1 dependent. Also, partial ablation of Akt activity is sufficient to suppress tumorigenesis and in vivo. These results may have a significant impact on cancer therapies, as analogs of rapamycin, an mTORC1 inhibitor, are already FDA approved as treatments to suppress the immune system. Using these rapamycin analogs as part of a combinatorial chemotherapeutic strategy may prove to be a very powerful tool indeed.; We also provide evidence demonstrating the ability of activated Akt to overcome the G2/M checkpoint, resulting in the acquisition of mutations. In addition, we analyzed the role of Akt in cell cycle exit, or senescence. We show that primary Akt-deficient MEFs senesce slower than wild type cells in response to oncogenic stimuli.; Further biochemical investigation is needed before patients are treated with mTORC1 or Akt inhibitors. Our results suggest that therapeutic strategies targeting Akt may lead to an increased cellular lifespan, albeit at a reduced rate. mTORC1 inhibitors may reduce the proliferation rate of cells but may inadvertently lead to protection from apoptosis as Akt activity will be increased due to ablation of the negative feedback loop. This pathway may hold great potential for targeted therapeutics and further research may help shed light on these key questions.