Multiple feed back loops exist in the regulation of Akt mTOR signaling. Essentially, p70 S6K phosphorylates and inhibits IRS 1, causing a negative feed back to Akt/mTOR signaling. By this mechanism, inhibition of mTOR signaling often results in activation of Akt and cancer cells might obtain resistance Lapatinib structure to mTOR inhibitors. But, in PC 3 cells curcumin inhibited both Akt and mTOR similarly. Furthermore, the inhibition of Akt phosphorylation at Thr308 happened much earlier than the inhibition of phosphorylation of Akt at Ser473, mTOR and other downstream components. Depending on these findings, it’s impossible that curcumin restricted Akt/mTOR axis by directly inhibiting mTOR. MAPKs, especially p38, have now been reported to be engaged in the inhibition of Akt signaling. Curcumin triggered Erk1/2, JNK, and p38 in Metastasis PC 3 cells, but the participation of MAPKs in the inhibition of Akt/mTOR signaling by curcumin was eliminated by the failure of specific inhibitors to revive Akt/mTOR phosphorylation. Having ignored the inhibition/activation of upstream kinases from the main inhibitory process, we turned to examine the possible involvement of protein phosphatases, particularly serine/threonine protein phosphatase since the phosphorylation and dephosphorylation that regulates the components of Akt/mTOR signaling pathway primarily occur at threonine or serine. PP1 and PP2A account for the majority of serine/threonine protein phosphatase activity in many cells. The PP1 inhibitor tautomycin exhibited only a very weak restoration of Akt/mTOR phosphorylation at a concentration greater than that required for inhibition of PP1. On another hand, calyculin An entirely solved curcumin mediated dephosphorylation of mTOR, Akt, S6, and 4e-bp1. Similar effect was observed for the expression of cyclin D1. More over, calyculin A successfully rescued the curcumin mediated inhibition of 3H leucine incorporation in PC 3 ARN-509 clinical trial cells. The result of okadaic acid was less potent but nevertheless significant, suggesting that curcumin mediated inhibition of Akt/mTOR signaling and cell growth is dependent on PP2A and/or unspecified calyculin A sensitive protein phosphatases. Curcumin has been found to activate Src homology 2 domain containing tyrosine phosphatase 2 in brain microglia. In yet another study, curcumin was proven to up regulate MKP5 to repress inflammatory responses in prostate cells. Here we discovered that curcumin also activated serine/threonine protein phosphatase activity in PC 3 cells. Those activities of protein phosphatases are subjected to multiple degrees of regulation, but, the exact mechanisms remains largely unknown. As an example, PP2A holoenzyme, which has a range of substrates, is made up of a wide number of regulatory subunits and a core heterodimmer of catalytic and scaffold subunits.