Statin-induced cellular effects mediated by the P2X7 receptor

摘要: Cholesterol-lowering statins have been shown to inhibit growth of different cancer cells both in vitro and vivo. Epidemiological studies also indicate a chemopreventive effect statins. We investigated the on Akt/protein kinase B signaling their sensitizing cytostatic drugs. It was found that insulinand drug-induced Akt phosphorylations nuclear translocation inhibited by pravastatin atorvastatin HepG2, A549 H1299 an mTOR dependent manner. Statins induced insulin receptor substrate 1 (IRS-1). In p53 wild-type (HepG2 A549) pretreatment with did not sensitized etoposide concentrations which stabilization. line our previous data, were attenuate etoposide-induced response. show p53-deficient cell (H1299) etoposide, doxorubicin 5-fluorouracil increased level apoptosis. Taken together we clearly demonstrate, mTOR–dependent, statin-induced inhibition phosphorylation localization sensitize However, this can be counteracted competent ability destabilize p53. Further address question possible anti-cancer effects tested possibility pAkt are mediated P2X7 receptor. low concentration decreased insulininduced phosphorylated nucleus. This seen within minutes inhibitors. Our results reveal via modulate insulin-induced epithelial cells. Furthermore, data regulate invastigated pancreatic lines. constitutiveand Panc-1 MIA PaCa2 synergy gemcitabineand 5 fluorouracil, apoptosis proliferation. P2X7-purinergic PaCa-2 Interestingly, Capan-2 cells, expressed levels, reduce levels nor them statin correlated NFkB Raf/MEK pathways. These might explained protein prenylation. Finally, mechanism underlying rapid Akt. A role PTEN as negative regulator suggested. Simultaneous activation PTEN, PHLPP1 2, calcineurin detected time frame where is abolished from model for how PHLPP control has suggests: prevents removing second messenger, PIP3, activates Akt, inactivates direct dephosphorylation. indicate, first time, activated simultaneously bound same substrate. Apparently phosphatases participated down-regulation coordinated action. Overall, these yield novel acts upon stimulation. LIST OF PUBLICATIONS I. Roudier E, Mistafa O, Stenius U. induce mammalian target rapamycin (mTOR)-mediated Molecular Cancer Therapeutics, 2006;5:2706–15 II. Hogberg Johan, ATP purinergic Biochemical Biophysical Research Communications, 2008;365:131-6 III. Akt/PKB [Submitted] IV. Ghalali A, Kadekar S, J, Statin-induced depletion correlates changes Calcineurin. [Manuscript] CONTENTS