Statins inhibit Akt/PKB signaling via P2X7 receptor in pancreatic cancer cells.
Cholesterol-lowering statins have been shown to inhibit growth of pancreatic cancer cells in vitro and in vivo. 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 NFkappaB 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.
Mistafa
Oras
O
Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Stenius
Ulla
U
D017209:Apoptosis; D000069059:Atorvastatin; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D005472:Fluorouracil / Q000494:pharmacology; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D034741:RNA, Small Interfering; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000502:physiology*; D058486:Receptors, Purinergic P2X7; D015398:Signal Transduction / Q000187:drug effects*; D000093542:Gemcitabine
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C546468:P2RX7 protein, human; D011758:Pyrroles; D034741:RNA, Small Interfering; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D003841:Deoxycytidine; D000069059:Atorvastatin; D051057:Proto-Oncogene Proteins c-akt; D005472:Fluorouracil; D000093542:Gemcitabine