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AMPK activation by stain suppresses endothelial ROS and apoptosis. A and B, AMPK activation suppresses endothelial ROS. Values represent mean S.E. from three independent experiments. , p 0.05 (control versus statin); , p 0.05 (statin versus statin plus AMPK-DN); ‡, p 0.05 (AMPK-CA versus AMPK-CA plus statin). C, AMPK activation by statin suppresses Ang-II-induced endothelial ROS. , p 0.05 (control versus Ang-II); , p 0.05 (Ang-II versus Ang-II plus statins); ‡, p 0.05 (Ang-II versus Ang-II plus statin plus compound C). D, AMPK activation by statin suppresses endothelial cell apoptosis triggered by high glucose (n 5; , p 0.01 (control versus HG); †, p 0.01 (HG versus HG plus statin); ‡, p 0.01 (HG plus statin versus HG plus statin plus AMPK-DN)). Control, normal glucose, 5 mmol/liter D-glucose); OG, osmotic control glucose (5 mmol/liter D-glucose 25 mmol/liter L-glucose); HG, 30 mmol/liter D-glucose; statin, 5 mol/liter statin; AMPK-DN, dominant negative mutants of AMPK.
Source publication
The AMP-activated protein kinase (AMPK) is reported to mediate the beneficial effects of statin on the vascular functions,
but the biochemical mechanisms are incompletely understood. The aim of the study was to determine how statin activates AMPK.
Exposure of confluent bovine aortic endothelial cells to simvastatin (statin) dose-dependently increas...
Citations
... For instance, AMPK inhibits fatty acid and cholesterol synthesis through direct phosphorylation of anabolic enzymes including Acetyl-CoA carboxylase (ACC) and HMG-CoA reductase (HMGR) [92]. While the AMPK pathway is traditionally thought of as a regulator of metabolism, recent studies have demonstrated that AMPK may play a significant part in maintaining normal endothelial function through AMPindependent activation of AMPK [75,[93][94][95][96]. LKB1 and the calcium/calmodulin-dependent kinase (CaMKK) are protein kinases that phosphorylate AMPK. ...
In addition to their lipid-lowering functions, statins elicit additional pleiotropic effects on apoptosis, angiogenesis, inflammation, senescence, and oxidative stress. Many of these effects have been reported in cancerous and noncancerous cells like endothelial cells (ECs), endothelial progenitor cells (EPCs) and human umbilical vein cells (HUVCs). Not surprisingly, statins' effects appear to vary largely depending on the cell context, especially as pertains to modulation of cell cycle, senescence, and apoptotic processes. Perhaps the most critical reason for this discordance is the bias in selecting the applied doses in various cells. While lower (nanomolar) concentrations of statins impose anti-senescence, and antiapoptotic effects, higher concentrations (micromolar) appear to precipitate opposite effects. Indeed, most studies performed in cancer cells utilized high concentrations, where statin-induced cytotoxic and cytostatic effects were noted. Some studies report that even at low concentrations, statins induce senescence or cytostatic impacts but not cytotoxic effects. However, the literature appears to be relatively consistent that in cancer cells, statins, in both low or higher concentrations, induce apoptosis or cell cycle arrest, anti-proliferative effects, and cause senescence. However, statins’ effects on ECs depend on the concentrations; at micromolar concentrations statins cause cell senescence and apoptosis, while at nonomolar concentrations statins act reversely.
... Reports suggest that statins also activate the AMPK signaling in cardiac muscle and show cardioprotective action. This signaling pathway is dependent on the RNS (reactive nitrogen species) and Ras-related C3 botulinum toxin substrate 1 (Rac1) [132][133][134]. Pitavastatin blocks Rac1 was shown in a mouse model of Dox cardiotoxicity and shows cardiac protective role via a reduction in the cardiac muscle apoptosis and regulates the constriction function. ...
Doxorubicin (Dox) is a secondary metabolite of the mutated strain of Streptomyces peucetius var. Caesius and belongs to the anthracyclines family. The anti-cancer activity of Dox is mainly exerted through the DNA intercalation and inhibiting topoisomerase II enzyme in fast-proliferating tumors. However, Dox causes cumulative and dose-dependent cardiotoxicity, which results in increased risks of mortality among cancer patients and thus limiting its wide clinical applications. There are several mechanisms has been proposed for doxorubicin-induced cardiotoxicity and oxidative stress, free radical generation and apoptosis are most widely reported. Apart from this, other mechanisms are also involved in Dox-induced cardiotoxicity such as impaired mitochondrial function, a perturbation in iron regulatory protein, disruption of Ca²⁺ homeostasis, autophagy, the release of nitric oxide and inflammatory mediators and altered gene and protein expression that involved apoptosis. Dox also causes downregulation of DNA methyltransferase 1 (DNMT1) enzyme activity which leads to a reduction in the DNA methylation process. This hypomethylation causes dysregulation in the mitochondrial genes like peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1-alpha (PGC‐1α), nuclear respiratory factor 1 (NRF‐1) and mitochondrial transcription factor A (TFAM) unit in the heart. Apart from DNA methylation, Dox treatment also alters the micro RNAs levels and histone deacetylase (HDAC) activity. Therefore, in the current review, we have provided a detailed update on the current understanding of the pathological mechanisms behind the well-known Dox-induced cardiotoxicity. Further, we have provided some of the most plausible pharmacological strategies which have been tested against Dox-induced cardiotoxicity.
... Statins are commonly prescribed lipid-lowering agents and they have been shown to activate AMPK in mouse myocardium by increased phosphorylation of Thr172 of the α1 subunit [69]. This activation of AMPK is dependent on reactive nitrogen species [109] and/or Rac1 [110], at least in endothelial cells. Rac1 inhibition was shown in a mouse model of DOX cardiotoxicity treated with pitavastatin, leading to attenuated myocyte apoptosis and improved contractile function [111]. ...
Doxorubicin is a commonly used chemotherapeutic agent for the treatment of a range of cancers, but despite its success in improving cancer survival rates, doxorubicin is cardiotoxic and can lead to congestive heart failure. Therapeutic options for this patient group are limited to standard heart failure medications with the only drug specific for doxorubicin cardiotoxicity to reach FDA approval being dexrazoxane, an iron-chelating agent targeting oxidative stress. However, dexrazoxane has failed to live up to its expectations from preclinical studies while also bringing up concerns about its safety. Despite decades of research, the molecular mechanisms of doxorubicin cardiotoxicity are still poorly understood and oxidative stress is no longer considered to be the sole evil. Mitochondrial impairment, increased apoptosis, dysregulated autophagy and increased fibrosis have also been shown to be crucial players in doxorubicin cardiotoxicity. These cellular processes are all linked by one highly conserved intracellular kinase: adenosine monophosphate–activated protein kinase (AMPK). AMPK regulates mitochondrial biogenesis via PGC1α signalling, increases oxidative mitochondrial metabolism, decreases apoptosis through inhibition of mTOR signalling, increases autophagy through ULK1 and decreases fibrosis through inhibition of TGFβ signalling. AMPK therefore sits at the control point of many mechanisms shown to be involved in doxorubicin cardiotoxicity and cardiac AMPK signalling itself has been shown to be impaired by doxorubicin. In this review, we introduce different agents known to activate AMPK (metformin, statins, resveratrol, thiazolidinediones, AICAR, specific AMPK activators) as well as exercise and dietary restriction, and we discuss the existing evidence for their potential role in cardioprotection from doxorubicin cardiotoxicity.
... Adenovirus KCNQ1-GFP (Genebank NM_000218) and adenovirus KCNE1 (Genebank BC046224) were designed and amplified by Vector Biolabs. Cell permeable TAT-conjugated cPKC activator (KAC1-1, SVEIWD Cys -Cys TAT [47][48][49][50][51][52][53][54][55][56][57] 35 , and a control peptide containing the HIV-TAT sequence (C1, TAT [47][48][49][50][51][52][53][54][55][56][57] 36 were gifts from KAI Pharmaceuticals (South San Francisco, CA). The cell permeable pseudo-RACK1 activator peptide (KKWKMRRNQFWIKIQRC-CSVEIWD, containing a disulfide bridge between 17 and 1, Tocris Bioscience) was diluted in water and applied to the extracellular media at 1 μM concentration. ...
... Adenovirus KCNQ1-GFP (Genebank NM_000218) and adenovirus KCNE1 (Genebank BC046224) were designed and amplified by Vector Biolabs. Cell permeable TAT-conjugated cPKC activator (KAC1-1, SVEIWD Cys -Cys TAT [47][48][49][50][51][52][53][54][55][56][57] 35 , and a control peptide containing the HIV-TAT sequence (C1, TAT [47][48][49][50][51][52][53][54][55][56][57] 36 were gifts from KAI Pharmaceuticals (South San Francisco, CA). The cell permeable pseudo-RACK1 activator peptide (KKWKMRRNQFWIKIQRC-CSVEIWD, containing a disulfide bridge between 17 and 1, Tocris Bioscience) was diluted in water and applied to the extracellular media at 1 μM concentration. ...
... on PKC, increasing kinase activity and expression [55][56][57] as well as decreasing cell viability 58 . To confirm the statin effects we observed on Rab5-cPKC-mediated internalization of KCNQ1/KCNE1 channels are not mediated by direct effects on viability or direct PKC expression or activation, we first measured cell viability using Trypan blue staining and a cell counter. ...
Statins are prescribed for prevention and treatment of coronary artery disease. Statins have different cholesterol lowering abilities, with rosuvastatin and atorvastatin being the most effective, while statins like simvastatin and fluvastatin having lower effectiveness. Statins, in addition to their cholesterol lowering effects, can prevent isoprenylation of Rab-GTPase proteins, a protein family important for the regulation of membrane-bound protein trafficking. Here we show that endosomal localization of Rab-GTPases (Rab5, Rab7 and Rab11) was inhibited in a statin-specific manner, with stronger effects by fluvastatin, followed by simvastatin and atorvastatin, and with a limited effect by rosuvastatin. Fluvastatin inhibition of Rab5 has been shown to mediate cPKC-dependent trafficking regulation of the cardiac delayed rectifier KCNQ1/KCNE1 channels. We observed statin-specific inhibition of channel regulation consistent with statin-specific Rab-GTPase inhibition both in heterologous systems and cardiomyocytes. Our results uncover a non-cholesterol-reducing statin-specific effect of statins. Because Rab-GTPases are important regulators of membrane trafficking they may underlie statin specific pleiotropic effects. Therefore, statin-specificity may allow better treatment tailoring.
... Several authors have also adduced evidence that administration of statins reduces the stability of membrane lipid rafts, thereby inhibiting the transduction of ROS-mediated signalling and downstream inflammatory pathways instigating cytokine and chemokine production (Hothersall et al., 2006;Wang, 2014). Statins also have the capacity positively to regulate mitochondrial biogenesis and oxidative phosphorylation via increasing the activity of AMPK, especially in an environment of chronic oxidative (Choi et al., 2008;Sun et al., 2006). ...
Background:
The blood-brain barrier acts as a highly regulated interface; its dysfunction may exacerbate, and perhaps initiate, neurological and neuropsychiatric disorders.
Methods:
In this narrative review, focussing on redox, inflammatory and mitochondrial pathways and their effects on the blood-brain barrier, a model is proposed detailing mechanisms which might explain how increases in blood-brain barrier permeability occur and can be maintained with increasing inflammatory and oxidative and nitrosative stress being the initial drivers.
Results:
Peripheral inflammation, which is causatively implicated in the pathogenesis of major psychiatric disorders, is associated with elevated peripheral pro-inflammatory cytokines, which in turn cause increased blood-brain barrier permeability. Reactive oxygen species, such as superoxide radicals and hydrogen peroxide, and reactive nitrogen species, such as nitric oxide and peroxynitrite, play essential roles in normal brain capillary endothelial cell functioning; however, chronically elevated oxidative and nitrosative stress can lead to mitochondrial dysfunction and damage to the blood-brain barrier. Activated microglia, redox control of which is mediated by nitric oxide synthases and nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, secrete neurotoxic molecules such as reactive oxygen species, nitric oxide, prostaglandin, cyclooxygenase-2, quinolinic acid, several chemokines (including monocyte chemoattractant protein-1 [MCP-1], C-X-C motif chemokine ligand 1 [CXCL-1] and macrophage inflammatory protein 1α [MIP-1α]) and the pro-inflammatory cytokines interleukin-6, tumour necrosis factor-α and interleukin-1β, which can exert a detrimental effect on blood-brain barrier integrity and function. Similarly, reactive astrocytes produce neurotoxic molecules such as prostaglandin E2 and pro-inflammatory cytokines, which can cause a 'leaky brain'.
Conclusion:
Chronic inflammatory and oxidative and nitrosative stress is associated with the development of a 'leaky gut'. The following evidence-based approaches, which address the leaky gut and blood-brain barrier dysfunction, are suggested as potential therapeutic interventions for neurological and neuropsychiatric disorders: melatonin, statins, probiotics containing Bifidobacteria and Lactobacilli, N-acetylcysteine, and prebiotics containing fructo-oligosaccharides and galacto-oligosaccharides.
... In bovine aortic endothelial cells Increased ROS and activates PKCζ-Thr 410/403 , liver kinase B1-Ser 428 , and AMPK Thr 172 . Choi et al. (2008) In muscles of mice Reduced ubiquinone by almost 50%. Muraki et al. (2012) Hoppeler (2016) In plantaris muscle of male Wistar rats Reduced mitochondrial DNA, cytochrome oxidase 1, nuclear respiratory factor 1, and maximal mitochondrial respiration. ...
... upstream kinase for the critical metabolic enzymes Acetyl-CoA carboxylase (ACC1 and ACC2) and HMGCR, reducing fat accumulation and cholesterol synthesis as well as the oncogenic transformation promoted by the dysregulation of these pathways [89]. Recently, several studies reported that AMPK is activated by statins in a broad selection of cancer types [88,[90][91][92][93]. ...
Background:
Modifications of lipid metabolism have been progressively accepted as a hallmark of tumor cells and in particular, an elevated lipogenesis has been described in various types of cancers.
Objective:
Important or deregulated activity of the mevalonate pathway has been demonstrated in different tumors and a wide range of studies have suggested that tumor cells are more dependent on the unceasing availability of mevalonate pathway metabolites than their non-malignant complements.
Method:
An overview of the state of the art of statins treatment on human cancer.
Results:
In recent times, a various action has been proposed for statins in different physiological and pathological conditions beyond anti-inflammation and neuroprotection activity. Statins have been shown to act through mevalonate-dependent and -independent mechanisms abling to affect several tissue functions and modulating specific signal transduction pathways that could account for statin pleiotropic effect. Based on their characteristics, statins represent ideal candidates for repositioning in cancer therapy.
Conclusion:
In this review article, we provide an overview of the current preclinical and clinical status of statins as antitumor agents. In addition, we evaluated various patents that describe the role of mevalonate pathway inhibitors and methods to determine if cancer cells are sensitive to statins treatment.
... It has been demonstrated that lovastatin treatment (1-25 µM, 24 h) impairs mitochondrial function, decreases cellular ADP/ATP ratios, and consequently activates LKB1/AMPK pathway [37]. Statins can rapidly activate AMPK via increased Thr-172 phosphorylation in vitro and in vivo [38][39][40]. ...
Regulation of lipid metabolism is essential for treatment and prevention of several chronic diseases such as obesity, diabetes, and cardiovascular diseases, which are responsible for most deaths worldwide. It has been demonstrated that the AMP-activated protein kinase (AMPK) has a direct impact on lipid metabolism by modulating several downstream-signaling components. The main objective of the present work was to evaluate the in vitro effect of a methanolic strawberry extract on AMPK and its possible repercussion on lipid metabolism in human hepatocellular carcinoma cells (HepG2). For such purpose, the lipid profile and the expression of proteins metabolically related to AMPK were determined on cells lysates. The results demonstrated that strawberry methanolic extract decreased total cholesterol, low-density lipoprotein (LDL)-cholesterol, and triglycerides levels (up to 0.50-, 0.30-, and 0.40-fold, respectively) while it stimulated the p-AMPK/AMPK expression (up to 3.06-fold), compared to the control. AMPK stimulation led to the phosphorylation and consequent inactivation of acetyl coenzyme A carboxylase (ACC) and inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the major regulators of fatty acids and cholesterol synthesis, respectively. Strawberry treatment also entailed a 4.34-, 2.37-, and 2.47-fold overexpression of LDL receptor, sirtuin 1 (Sirt1), and the peroxisome proliferator activated receptor gamma coactivator 1-alpha (PGC-1α), respectively, compared to control. The observed results were counteracted by treatment with compound C, an AMPK pharmacological inhibitor, confirming that multiple effects of strawberries on lipid metabolism are mediated by the activation of this protein.
... UA-induced AMPK activation may be also mediated by UA-associated oxidative and nitrosative stress (this study). It has been reported that reactive oxygen species and reactive nitrogen species may activate AMPK [54][55][56]. Nitric oxide may also activate ataxia telangiectasia mutated (ATM) kinase, DNA damage response kinase [57], that in turn activate AMPK and promote cytotoxic autophagy in MCF-7 cells [58]. ATM may be also activated directly by ROS [59]. ...
Plant-derived pentacyclic triterpenotids with multiple biological activities are considered as promising candidates for cancer therapy and prevention. However, their mechanisms of action are not fully understood. In the present study, we have analyzed the effects of low dose treatment (5–20 µM) of ursolic acid (UA) and betulinic acid (BA) on breast cancer cells of different receptor status, namely MCF-7 (ER⁺, PR+/−, HER2⁻), MDA-MB-231 (ER⁻, PR⁻, HER2⁻) and SK-BR-3 (ER⁻, PR⁻, HER2⁺). UA-mediated response was more potent than BA-mediated response. Triterpenotids (5–10 µM) caused G0/G1 cell cycle arrest, an increase in p21 levels and SA-beta-galactosidase staining that was accompanied by oxidative stress and DNA damage. UA (20 µM) also diminished AKT signaling that affected glycolysis as judged by decreased levels of HK2, PKM2, ATP and lactate. UA-induced energy stress activated AMPK that resulted in cytotoxic autophagy and apoptosis. UA-mediated elevation in nitric oxide levels and ATM activation may also account for AMPK activation-mediated cytotoxic response. Moreover, UA-promoted apoptosis was associated with decreased pERK1/2 signals and the depolarization of mitochondrial membrane potential. Taken together, we have shown for the first time that UA at low micromolar range may promote its anticancer action by targeting glycolysis in phenotypically distinct breast cancer cells.
... 14,15 AMP-activated protein kinase (AMPK), a cellular energy sensor that mediates metabolic homeostasis under environmental stress conditions, was recently reported to be activated by statins. [16][17][18][19][20] Autophagy inhibition enhances the anticancer effects of statins in digestive malignancies. 18,21 AMPK activation has been reported to suppress cell proliferation in non-tumor and tumor cells by regulating cell cycle progression or inhibiting protein synthesis. ...
Hepatocellular carcinoma (HCC) is characterized by a poor prognosis and is one of the leading causes of cancer-related death worldwide. Simvastatin, an HMG-CoA reductase inhibitor, which decreases cholesterol synthesis by inhibiting mevalonate pathways and is widely used to treat cardiovascular diseases. Simvastatin exhibits anticancer effects against several malignancies. However, the molecular mechanisms underlying the anticancer effects of simvastatin on HCC are still not well understood. In this study, we demonstrated simvastatin-induced G0/G1 arrest by inducing p21 and p27 accumulation in HepG2 and Hep3B cells. Simvastatin also promoted AMP-activated protein kinase (AMPK) activation, which induced p21 upregulation by increasing its transcription. Consistent with this finding, we found genetic silencing of AMPK reduced p21 expression; however, AMPK silencing had no effect on p27 expression in HCC cells. Simvastatin decreased Skp2 expression at the transcriptional level, which resulted in p27 accumulation by preventing proteasomal degradation, an effect mediated by signal transducer and activator of transcription 3 (STAT3) inhibition. Constitutive STAT3 activation maintained high-level Skp2 expression and lower level p27 expression and significantly prevented G0/G1 arrest in simvastatin-treated HCC cells. Mevalonate decreased simvastatin-induced AMPK activation and rescued phospho-STAT3 and Skp2 expression in HCC cells, which resulted in the prevention of G0/G1 arrest through inhibition of p21 and p27 accumulation. Moreover, simvastatin significantly decreased tumor growth in HepG2 xenograft mice. Consistently, we found that simvastatin also increased p21 and p27 expression in tumor sections by reducing Skp2 expression and inducing AMPK activation and STAT3 suppression in the same tumor tissues. Taken together, these findings are demonstrative of the existence of a novel pathway in which simvastatin induces G0/G1 arrest by upregulating p21 and p27 by activating AMPK and inhibiting the STAT3–Skp2 axis, respectively. The results identify novel targets that explain the beneficial anticancer effects of simvastatin treatment on HCC in vitro and in vivo.
