Numerous feed back loops exist in the regulation of Akt mTOR signaling. Significantly, p70 S6K phosphorylates and inhibits IRS 1, causing a negative feed-back to Akt/mTOR signaling. By this mechanism, inhibition of mTOR signaling often contributes to activation of Akt and cyst cells could acquire resistance supplier ARN-509 to mTOR inhibitors. However, in PC 3 cells curcumin inhibited equally mTOR and Akt similarly. Moreover, the inhibition of Akt phosphorylation at Thr308 happened much earlier than the inhibition of phosphorylation of Akt at Ser473, mTOR and other downstream components. According to these findings, it is impossible that curcumin inhibited Akt/mTOR axis by directly inhibiting mTOR. MAPKs, specially p38, have now been reported to be engaged in the inhibition of Akt signaling. Curcumin triggered Erk1/2, JNK, and p38 in Skin infection PC 3 cells, but the effort of MAPKs in the inhibition of Akt/mTOR signaling by curcumin was ruled out by the failure of specific inhibitors to revive Akt/mTOR phosphorylation. Having ignored the inhibition/activation of upstream kinases in the major inhibitory mechanism, we considered examine the possible involvement of protein phosphatases, specifically serine/threonine protein phosphatase since the phosphorylation and dephosphorylation that regulates the components of Akt/mTOR signaling pathway mostly occur at threonine or serine. PP1 and PP2A account fully for the majority of serine/threonine protein phosphatase activity in most cells. The PP1 chemical tautomycin displayed only a very weak repair of Akt/mTOR phosphorylation at a concentration higher than that needed for inhibition of PP1. On the other hand, calyculin A fully reversed curcumin mediated dephosphorylation of Akt, mTOR, S6, and 4E BP1. Similar result was seen for the expression of cyclin D1. Furthermore, calyculin A successfully saved the curcumin mediated inhibition of 3H leucine incorporation in PC 3 Lapatinib solubility cells. The consequence of okadaic acid was less-potent but still significant, suggesting that curcumin mediated inhibition of Akt/mTOR signaling and cell proliferation depends on PP2A and/or unspecified calyculin A protein phosphatases. Curcumin is found to activate Src homology 2 domain containing tyrosine phosphatase 2 in brain microglia. In another study, curcumin was proven to up regulate MKP5 to repress inflammatory responses in prostate cells. Here we found that curcumin also activated serine/threonine protein phosphatase activity in PC 3 cells. The activities of protein phosphatases are afflicted by multiple levels of regulation, but, the actual mechanisms is still largely unknown. For example, PP2A holoenzyme, that has a diversity of substrates, consists of a core heterodimmer of catalytic and scaffold subunits and a broad number of regulatory subunits.