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. 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. .

Emodin Sensitizes Hepatocellular Carcinoma Cells to the Anti-Cancer Effect of Sorafenib through Suppression of Cholesterol Metabolism

“…Evidence has emerged to indicate that increased lipids and cholesterol, which are correlated with elevated oncogenic growth signaling, such as PI3K-AKT and MAPK signaling in cancer cells, are now considered a hallmark of cancer aggressiveness [ 14 , 20 ]. Indeed, many reports have shown that cholesterol-lowering drugs, such as atorvastatin, lovastatin, and simvastatin, inhibit cancer cell growth and invasiveness via the suppression of oncogenic signaling in HCC, melanoma, glioma, and ovarian cancer [ 21 , 22 , 23 , 24 ]. On this basis, the inhibitory effect of emodin on oncogenic growth signaling in HCC cells was evaluated.…”

Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine

“…In experimental systems, statins elicit a variety of pleotropic anti-neoplastic, in addition to cholesterol-lowering, effects. Statins inhibit oncogenic pathways, including Myc, 156 Akt, 157,158 integrin and Rho-dependent kinase, 159 nuclear factor κB (NF-κB), and tumor necrosis factor (TNF)-mediated IL6 production, 160 and Hippo pathway effector TAZ, and extracellular signal–regulated kinase 1/2 (ERK1/2), 161 whereas adenosine monophosphate-activated protein kinase (AMPK) and p38/mitogen-activated protein kinase (MAPK) pathways are activated,. 162,163 and p53-dependent apoptosis is induced 164 (Figure 3).…”

Statin Use and the Risk of Hepatocellular Carcinoma: A Meta-Analysis of Observational Studies

“…Moreover, in vivo studies showed promising results in antitumor effects such as the inhibition of cell proliferation and the promotion of tumor cell differentiation in various animal models [17,18]. Statins perhaps help to prevent HCC by suppressing oncogenic pathways including Rho-dependent kinase [19], tumor necrosis factor (TNF)-mediated interleukin (IL6) production [20], Akt [21], Myc-medicated cell proliferation, and so on [22] (Figure 1). The beneficial effects of statin use have ubiquitously been reported for liver cancer patients.…”