Statin-induced cellular effects mediated by the P2X7 receptor
Year: 2009
Type: dissertation
Abstract: Cholesterol-lowering statins have been shown to inhibit growth of \ndifferent cancer cells both in vitro and in vivo. Epidemiological studies \nalso indicate a chemopreventive effect of statins. We have investigated \nthe effect of statins on Akt/protein kinase B signaling and their \nsensitizing effect of cytostatic drugs. \n \n \n \nIt was found that insulin- and cytostatic drug-induced Akt \nphosphorylations and nuclear translocation was inhibited by pravastatin \nand atorvastatin in HepG2, A549 and H1299 cells in an mTOR dependent \nmanner. Statins also induced mTOR dependent phosphorylations of insulin \nreceptor substrate 1 (IRS-1). In p53 wild-type cells (HepG2 and A549) \npretreatment with statins did not sensitized cells to etoposide in \nconcentrations which induced p53 stabilization. In line with our previous \ndata, statins were found to attenuate the etoposide-induced p53 response. \nWe also show that in a p53-deficient cell line (H1299) pretreatment with \natorvastatin sensitized cells to etoposide, doxorubicin and \n5-fluorouracil and increased the level of apoptosis. Taken together we \nclearly demonstrate, that an mTOR dependent, statin-induced inhibition of \nAkt phosphorylation and nuclear localization sensitize cells to \ncytostatic drugs. However, this effect can be counteracted in p53 \ncompetent cells by the ability of statins to destabilize p53. \n \n \n \nFurther we address the question of possible anti-cancer effects of \nstatins. We tested the possibility that statin-induced effects on nuclear \npAkt are mediated by the P2X7 receptor. We show that low concentration of \natorvastatin decreased the level of insulin-induced phosphorylated Akt in \nthe nucleus. This effect was seen within minutes and was inhibited by \nP2X7 inhibitors. Our results reveal that statins via the P2X7 receptor \nmodulate insulin-induced Akt signaling in epithelial cells. Furthermore, \nour data indicate that P2X7 regulate nuclear pAkt in epithelial cells. \n \n \n \nWe also invastigated the effect of statins in pancreatic cancer cell \nlines. We found that atorvastatin decreased constitutive- and \ninsulin-induced pAkt in Panc-1 and MIA PaCa-2 cells. Statins also \ninhibited pAkt in synergy with gemcitabine- and 5 fluorouracil, and \nsensitized cells to apoptosis and inhibited cell proliferation. It was \nalso found that the P2X7-purinergic receptor mediated the effects of \nstatins in Panc-1 and MIA PaCa-2 cells. Interestingly, in Capan-2 cells, \nwhich expressed P2X7 in low levels, statins did not reduce pAkt levels \nnor did statins sensitize them to cytostatic drugs. However, statin \ninhibited the growth of Capan-2 cells and this correlated to inhibition \nof NFkB and Raf/MEK pathways. These effect might be explained by an \ninhibited protein prenylation. \n \n \n \nFinally, we investigated the mechanism underlying the rapid inhibition of \nnuclear Akt. A role of PTEN as a negative regulator was suggested. \nSimultaneous activation of PTEN, PHLPP1 and 2, and calcineurin was \ndetected in the time frame where pAkt is inhibited and abolished from \nnucleus. A model for how PTEN and PHLPP control Akt signaling has been \nsuggests: PTEN prevents activation by removing the second messenger, \nPIP3, that activates Akt, and PHLPP inactivates Akt by direct \ndephosphorylation. Our data indicate, for the first time, that PTEN and \nPHLPP were activated simultaneously and bound the same substrate. \nApparently both phosphatases participated in the down-regulation of \nnuclear pAkt in a rapid and coordinated action. Overall, these studies yield a novel mechanism by which Akt acts upon \nstatin stimulation.
Source: Figshare
Author: Oras Mistafa
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1693474170