Statins inhibit Akt/PKB signaling via P2X7 receptor in pancreatic cancer cells

Oras Mistafa , Ulla Stenius

Cholesterol-lowering statins have been shown to inhibit growth of pancreatic cancer cells and Epidemiological studies also indicate a chemopreventive effect of statins. We have investigated the effect of statins on Akt/protein kinase B signaling. We found that atorvastatin decreased constitutive- and insulin-induced pAkt in Panc-1 and MIA PaCa-2 cells. Statins also inhibited pAkt in combination with gemcitabine- and 5 fluorouracil, and sensitized cells to gemcitabine- and 5 fluorouracil-induced apoptosis and inhibition of cell proliferation. In line with our previous data, it was found that the P2X7-purinergic receptor mediated the effects of statins in Panc-1 and MIA PaCa-2 cells. Thus, experiments employing P2X7 siRNA and inhibitors supported an involvement of P2X7. In Capan-2 cells, which expressed P2X7 in low levels, statins did not reduce pAkt levels nor did statins sensitize them to cytostatic drugs. However, statin inhibited the growth of Capan-2 cells and this correlated to inhibition of NFκB and Raf/MEK pathways. As shown previously, these latter effects can be explained by an inhibited protein prenylation. Our data suggest that statins primarily target a functional P2X7-Akt signaling in pancreatic cancer cells. By targeting the P2X7-Akt axis, statins can sensitize pancreatic cancer cells to chemotherapeutic drugs. Our data are also in line with a role for P2X7 in the chemopreventive effect of statins on pancreatic cancer.

Mots clés: HMG-CoA; 5-Fu; PI3K; GSK3β; siRNA; pAkt Ser473; pAkt Thr308; pGSK3β Ser9; NF-κB; MAPK; P2X; P2X7; HEK; o-ATP; PARP; Atorvastatin; Akt; Chemotherapy; Pancreatic cancer

Oras Mistafa, Ulla Stenius. Statins inhibit Akt/PKB signaling via P2X7 receptor in pancreatic cancer cells. Biochemical Pharmacology, 2009, 78 (9), pp.1115. ⟨10.1016/j.bcp.2009.06.016⟩. ⟨hal-00519078⟩