title: Atorvastatin Decreases HBx-Induced Phospho-Akt in Hepatocytes via P2X Receptors.
abstract: Hepatocellular carcinoma (HCC) is rated as the fifth most common malignancy and third in cancer-related deaths worldwide. Statins, HMG-CoA reductase inhibitors, are potent cholesterol-lowering drugs, and recent epidemiologic evidence suggests that statins prevent aggressive HCC development. Previous experiments revealed that statins downregulate phosphorylated Akt (pAkt). Here, it is demonstrated that atorvastatin decreases nuclear pAkt levels in pancreatic and lung cancer cell lines within minutes, and this rapid effect is mediated by the purinergic P2X receptors. Akt is upregulated by hepatitis viruses and has oncogenic activity in HCC; therefore, we tested the possibility that the P2X-Akt pathway is important for the anticipated anticancer effects of statins in hepatocytes. Atorvastatin decreased hepatitis B virus X protein- and insulin-induced pAkt and pGsk3β (Ser9) levels. Furthermore, Akt-induced lipogenesis was counteracted by atorvastatin, and these statin-induced effects were dependent on P2X receptors. Statin also decreased proliferation and invasiveness of hepatocytes. These data provide mechanistic evidence for a P2X receptor-dependent signaling pathway by which statins decrease pAkt, its downstream phosphorylation target pGsk3β, and lipogenesis in hepatocytes.Implications:The Akt pathway is deregulated and may act as a driver in HCC development; the P2X-Akt signaling pathway may have a role in anticancer effects of statins.Mol Cancer Res; 15(6); 714-22. ©2017 AACR.
authors.affiliation: Institute of Environment Medicine. Karolinska Institutet, Stockholm, Sweden. aram.ghalali@ki.se.
authors.forename: Aram
authors.initials: A
authors.lastname: Ghalali
authors.affiliation: Institute of Environment Medicine. Karolinska Institutet, Stockholm, Sweden.
authors.forename: Javier
authors.initials: J
authors.lastname: Martin-Renedo
authors.affiliation: Institute of Environment Medicine. Karolinska Institutet, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Högberg
authors.affiliation: Institute of Environment Medicine. Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ulla
authors.initials: U
authors.lastname: Stenius
mesh_terms: D000069059:Atorvastatin / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D058469:Receptors, Purinergic P2X / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D007328:Insulin; C546468:P2RX7 protein, human; D058469:Receptors, Purinergic P2X; D058486:Receptors, Purinergic P2X7; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D000069059:Atorvastatin; D051057:Proto-Oncogene Proteins c-akt