Abstract 1042: Balance between several phosphatases is crucial for statin- and ATP-induced depletion of nuclear pAkt in prostatic cancer cells

Abstract

Abstract We have previously shown that cholesterol-lowering drugs, statins, or extracellular ATP, induce a complex and coordinated response in insulin-stimulated non-small cell lung cancer cells (A549), leading to depletion of nuclear phosphorylated Akt (pAkt). The response involved activation of protein/lipid phosphatases PTEN, PHLPP1 and −2, PP2A and calcineurin (J Biol Chem, 285, 27900, 2010). As Akt might be critical for prostatic cancer (PC) development and statins may prevent aggressive PC the effects of statins and ATP on Akt signaling in PC cells was studied. It was found that atorvastatin in micromolar concentrations decreased constitutive levels of pAkt in DU145 and 22RV1 cells. The effect was associated with a decreased phosphorylation of downstream targets of pAkt. Furthermore, we found that insulin-induced pAkt was inhibited by atorvastatin. Our previous data indicated that PTEN and PHLPP are essential for depletion of nuclear pAkt. In line with this no down-regulation of nuclear Akt and its downstream targets was induced by statins in PTEN deficient LNCaP cells. However, the statin-induced down-regulation of nuclear Akt was restored when cells were transfected for PTEN. We also transfected PTEN deficient PC3 cells with PTEN. However, in this cell line PTEN transfection did not restore the capacity of statins to deplete nuclear pAkt. Instead, we found that in PC3 cells the PTEN transfection lowered levels of PHLPP2 and PHLPP1. When the cells were transfected for both PTEN and PHLPP2 the capacity of statins to deplete nuclear pAkt was restored in PC3 cells. The crosstalk between PHLPP and PTEN was further studied in LNCap, PC3, 22RV1 cells and it was found that increasing PTEN levels depressed the levels of PHLPP 1 and 2 and vice versa. The similar cross talk was also observed between PHLPP1 and 2. These data indicate that a balance between different phosphatases is essential for statin-induced depletion of nuclear Akt. This might be due to the fact that formation of complexes between Akt and different phosphatases is needed for the depletion of nuclear pAkt. Our data suggest that a well-controlled balance between essential phosphatases is needed for nuclear pAkt depletion. This balance seems disturbed in many prostate cancer cell lines. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1042. doi:10.1158/1538-7445.AM2011-1042