Inhibition of AMPK-dependent autophagy enhances in vitro antiglioma effect of simvastatin

Misirkić, Maja; Janjetović, Kristina; Vučićević, Ljubica; Tovilović, Gordana; Ristić, Biljana; Vilimanovich, Urosh; Harhaji-Trajković, Ljubica; Šumarac-Dumanović, Mirjana; Micić, Dragan; Bumbaširević, Vladimir; Trajkovič, Vladimir

doi:10.1016/j.phrs.2011.08.003

Cited by 52 publications

(45 citation statements)

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“…50 Our findings are consistent with the recent studies showing that statin inhibits mTOR and its substrate S6K. 47,51 To our knowledge, the present study provides the first evidence that ATO limits hypertensive LV remodeling possibly by inducing autophagy via mTOR inhibition.…”

Section: Discussionsupporting

confidence: 91%

Augmentation of autophagy by atorvastatin via Akt/mTOR pathway in spontaneously hypertensive rats

Wang

Qian

et al. 2015

Hypertens Res

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Autophagy is activated in hypertension-induced cardiac hypertrophy. However, the mechanisms and significance of an activated autophagy are not clear. This study was designed to determine the role of atorvastatin (ATO) in cardiac autophagy and associated benefits on cardiac remodeling and left ventricular function in spontaneously hypertensive rats (SHRs). Twenty-eight male SHRs at 8 weeks of age were randomized to treatment with vehicle (saline solution; SHR+V) or ATO (SHR+ATO; 50 mg kg(-1) per day) for 6 or 12 months. Age-matched male Wistar-Kyoto (WKY) rats were used as normotensive controls. Cardiac magnetic resonance was used to evaluate cardiac function and structure. Compared with WKY rats, SHRs showed significant left ventricle (LV) dysfunction, remodeling and increases in cardiomyocyte size, which were all attenuated by 6 and 12 months of ATO treatment. Compared with WKY rats, autophagy was activated in the hearts of SHRs and this effect was amplified by chronic ATO treatment, particularly following 12 months of treatment. Protein expression levels of microtubule-associated protein-1 light chain 3-II and beclin-1, the biomarkers of an activated cardiac autophagy, were significantly elevated in ATO-treated versus vehicle-treated SHRs and control WKY rats. Cardiac Akt and phosphorylated mammalian target of rapamycin (mTOR) expression were also increased in the hearts of SHR versus WKY rats, and this effect was attenuated by ATO treatment. These findings suggest that ATO-mediated improvements in LV function and structure in SHRs may be, in part, through its regulation of cardiac autophagy via the Akt/mTOR pathway.

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Section: Discussionsupporting

confidence: 91%

Augmentation of autophagy by atorvastatin via Akt/mTOR pathway in spontaneously hypertensive rats

Wang

Qian

et al. 2015

Hypertens Res

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“…Primarily AMPK activates p53 transcriptional activity leading to classical cell cycle inhibition, reducing tumor growth through p21 CIP1 and p27 KIP1 activation (Jones et al, 2005). AMPK activation also downregulates mTOR signaling resulting in decreased protein synthesis and G2 block, whilst also releasing its constraint on autophagy, increasing glioma survival during chemotherapy (Vucicevic et al, 2009; Misirkic et al, 2012). Unresolved stress over prolonged periods can also result in increased apoptosis and therefore decreased viability.…”

Section: Amp-activated Protein Kinase: a Coordinator Of Energy Metabomentioning

confidence: 99%

Metabolic Reprogramming in Glioma

Strickland

Stoll

2017

Front. Cell Dev. Biol.

256

269

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Many cancers have long been thought to primarily metabolize glucose for energy production—a phenomenon known as the Warburg Effect, after the classic studies of Otto Warburg in the early twentieth century. Yet cancer cells also utilize other substrates, such as amino acids and fatty acids, to produce raw materials for cellular maintenance and energetic currency to accomplish cellular tasks. The contribution of these substrates is increasingly appreciated in the context of glioma, the most common form of malignant brain tumor. Multiple catabolic pathways are used for energy production within glioma cells, and are linked in many ways to anabolic pathways supporting cellular function. For example: glycolysis both supports energy production and provides carbon skeletons for the synthesis of nucleic acids; meanwhile fatty acids are used both as energetic substrates and as raw materials for lipid membranes. Furthermore, bio-energetic pathways are connected to pro-oncogenic signaling within glioma cells. For example: AMPK signaling links catabolism with cell cycle progression; mTOR signaling contributes to metabolic flexibility and cancer cell survival; the electron transport chain produces ATP and reactive oxygen species (ROS) which act as signaling molecules; Hypoxia Inducible Factors (HIFs) mediate interactions with cells and vasculature within the tumor environment. Mutations in the tumor suppressor p53, and the tricarboxylic acid cycle enzymes Isocitrate Dehydrogenase 1 and 2 have been implicated in oncogenic signaling as well as establishing metabolic phenotypes in genetically-defined subsets of malignant glioma. These pathways critically contribute to tumor biology. The aim of this review is two-fold. Firstly, we present the current state of knowledge regarding the metabolic strategies employed by malignant glioma cells, including aerobic glycolysis; the pentose phosphate pathway; one-carbon metabolism; the tricarboxylic acid cycle, which is central to amino acid metabolism; oxidative phosphorylation; and fatty acid metabolism, which significantly contributes to energy production in glioma cells. Secondly, we highlight processes (including the Randle Effect, AMPK signaling, mTOR activation, etc.) which are understood to link bio-energetic pathways with oncogenic signals, thereby allowing the glioma cell to achieve a pro-malignant state.

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“…Antiglioma effect [136] Rhabdomyolysis, myopathy, liver dysfunction, endocrine function of 80 mg simvastatin daily over 6 months. Brain MRIs were performed at months 4, 5 and 6 of simvastatin treatment.…”

Section: Statinsmentioning

confidence: 99%

“…Some data suggest that atorvastatin reduced the pro-tumorigenic effects of microglia on glioma migration and invasion by reducing the microglial expression of membrane type 1 metalloproteinase (MT1-MMP) [135]. Other authors suggest that simvastatin autophagy inhibition enhances antiglioma effects [136]. Preclinical studies on statins are identifying new nonselective statin targets that provide a basis for the development of new targeted anticancer drugs.…”

Section: Primary Brain Tumorsmentioning

confidence: 99%