title: Statins exhibit anticancer effects through modifications of the pAkt             signaling pathway.
abstract: Statins are cholesterol lowering drugs that exhibit antitumor effects in             several in vitro and in vivo models, and epidemiological studies indicate that             statins prevent cancer. However, the molecular mechanism underlying the effects             of statins still needs to be elucidated. We previously demonstrated that single             doses of different statins rapidly affect Akt signaling via the purinergic receptor             P2X7. In particular, statins down-regulated nuclear pAkt. Here, we report that             long-term treatment of A549 cells with high concentrations of statins (15-75 µM)             selects cell sub-populations exhibiting altered P2X receptor expression, signs             of increased PTEN activity, enhanced PHLPP2, decreased PI3K p110β and inhibited             downstream pAkt signaling. Furthermore, the nuclear accumulation of pAkt in response             to insulin was inhibited in selected cells. Statin-selected cells displayed reduced             proliferation rate and were more vulnerable to etoposide- and 5-fluorouracil-elicited             cytotoxic effects. The stability of a selected phenotype (50 µM) was tested for             three weeks in the absence of statins. This resulted in a reversal of some, but             not all alterations. Importantly, the truncated nuclear insulin response was retained.             We conclude that long-term treatment with high doses of statins selects cells             exhibiting stable alterations in insulin-Akt signaling and which are vulnerable             to DNA damage. Our studies strengthen the hypothesis that an altered Akt signaling             has a role in chemopreventive effects of statins.
authors: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: Erica
authors: E
authors: Miraglia
authors: Johan
authors: J
authors: Högberg
authors: Ulla
authors: U
authors: Stenius
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000069059:Atorvastatin; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D005047:Etoposide; D005472:Fluorouracil / Q000494:pharmacology; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D058469:Receptors, Purinergic P2X / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007328:Insulin; D011758:Pyrroles; D058469:Receptors, Purinergic P2X; D005047:Etoposide; D000069059:Atorvastatin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C541572:PHLPP2 protein, human; D010749:Phosphoprotein Phosphatases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D005472:Fluorouracil