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We and the others have previously shown that activation of GSK3B kinase plays a part in on-set of senescence. Especially, we showed that activation of GSK3B phosphorylates the HIRA histone chaperone, thus localizing this protein to PML bodies and instigating the forming of SAHF. Here we provide evidence that activated PIK3CA/AKT suppresses RASG12V caused Dasatinib HIRA relocalization and development of SAHF through its capability to inhibit and phosphorylate GS3KB. The significance of the PIK3CA/AKT GSK3B signaling axis in human cancer is underscored by our finding that a higher level of AKTpS473 or GSK3BpS9 is just a predictor of poor survival in human pancreatic cancer, independent of other common prognostic indicators. Next, activated RAS and activated PIK3CA/AKT antagonize one another through mTOR signaling. mTOR is well documented Metastatic carcinoma to become a potent repressor of autophagy. Activated AKT1 had been able to activate mTOR even in the presence of activated RAS, probably describing the capability of mAKT1 to prevent RASG12V induced autophagy, while mtor activity is inhibited by activated RAS to increase senescence and upregulate autophagy. The efficient mTOR inhibitor, rapamycin, reactivated RAS senescence, to affirm this in vivo, in rats haboring activated PIK3CA/AKT and activated RAS signaling. We consider that activated PIK3CA/AKT curbs RASinduced senescence through its capability to intersect with and antagonize many outputs of serious activated RAS, including repression of mTOR, service of GSK3B and upregulation of p16INK4a. TMA evaluation of human pancreatic cancer underscored GSK3B and mTOR as important targets within this disease, while triggered PIK3CA/AKT signaling is well known to possess several targets in the cell. Phosphorylation of most three proteins was significantly directly related, and high phosphorylation of every protein is just a predictor of poor Decitabine patient survival. Thus, the PIK3CA/AKTGSK3B/mTOR axis is an essential driver of illness outcome in human pancreatic cancer. While activation of AKT1 disadvantaged RASG12V induced senescence in vitro by a minimum of three conditions, it did not totally remove activated RAS induced senescence, as measured by proliferation arrest. On another hand, inactivation of PTEN did by-pass activated RAS caused senescence like arrest in vivo and caused an extraordinary acceleration of tumorigenesis. There are many possible explanations of this difference between the in vitro and in vivo models, including differences between cell types, use of RASG12V in vitro and RASG12D in vivo and effect of cellular micro-environment in vivo. It is also important to notice that in the mouse model, we can't conclude that inactivation of PTEN is sufficient to abrogate senescence in every of the RASG12D expressing cells. Rather, inactivation of PTEN might destroy the program enough to help total escape from senescence, but only in cooperation with additional selected and acquired mutations.