The Akt protein kinase, comprised of 3 isoforms, is a direct downstream ef fector of PI3K, which turns into fully activated by phos phorylation on the T308 and S473 web-sites. Activated Akt is often observed in poorly differentiated tumors wherever it bridges the link concerning numerous oncogenic re ceptors and pro survival cellular functions generating the tumor cells highly invasive and much less responsive to chemo therapeutic medication. The Akt effects on aberrant cell survival are mediated from the regulation of the number of essential downstream proteins that have been implicated in apoptosis and anoikis like Lousy, Caspase9, IKK, Mdm2 and FHKR. Akt can be associated with cell cycle regulation by phosphorylation and inactivation in the cyclin dependent kinase inhibitors p21 and p27 kip1.
Constitutively ac tivated Akt has been linked to epithelial to mesenchymal transition by regulating MMPs resulting in re duced cell to cell adhesion, improved motility and inva sion. It’s also been reported that Akt driven EMT may possibly confer the motility required for malignant progression and dissemination i thought about this of cancer cells to distant organs. Lately, we identified a brand new pathway by which TGFB PKA PP2A signaling deactivates Akt phosphorylation major to downregulation of IAPs, XIAP and survivin in colorectal cancer cells. The broad roles of this enzyme in cancer have estab lished Akt as an interesting therapeutic candidate in cancer. Compact molecule inhibitors of the PI3K Akt pathway are be ing designed for clinical use. Quite a few Akt inhibitors are actually synthesized, such as MK 2206, a novel allosteric kinase inhibitor of Akt.
MK 2206 binds towards the pleckstrin homology domain of Akt and thereby in hibits PDK1 binding and activation read the article of Akt. This outcomes in adjust in confirmation of Akt and its inability to localize to your plasma membrane. MK 2206 has proven promising preclinical action and is presently undergoing phase II clinical evaluation. Despite the fact that the specific mecha nisms underlying the anti cancer activity of MK 2206 stay to become fully elucidated, MK 2206 continues to be proven to induce cell cycle arrest and apoptosis. We now report that MK 2206 induces anti tumor ac tivity in the subset of human CRC cell lines characterized by their dependence on IGF1R signaling which results in PI3K Akt upregulation for cell survival. Strikingly, publicity to MK 2206 resulted from the generation of 2 mechanisms of cell death, which haven’t previously been documented, for this drug.
The MK 2206 dependent cell death of IGF1R dependent CRC cells in vitro and in vivo was characterized by Apoptosis Inducing Aspect in duction and its mitochondria to nuclear translocation, that’s known to induce caspase independent cell death. Moreover, MK 2206 dependent cell death was also characterized by the inactivation in the cytoskeletal organizing protein Ezrin at T567 top for the loss of Inhibitor of Apoptosis household protein XIAP.