Probucol suppresses human glioma cell proliferation in vitro via ROS production and LKB1-AMPK activation

Jiang, Yongsheng; Jing-an, Lei; Fang, Feng; Liang, Qiansheng; Wang, Furong

doi:10.1038/aps.2014.88

Cited by 9 publications

(6 citation statements)

References 29 publications

(32 reference statements)

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“…In addition, probucol was shown to possess anti-inflammatory, anti-fibrotic, and anti-oxidative effects [ 23 , 24 ] to delay the progress of early diabetic nephropathy [ 23 , 25 ]. Jiang et al [ 26 ] showed that probucol markedly increased the ROS production and inhibited lipoprotein lipid oxidation. Moreover, in a diabetic nephropathy model, probucol significantly reduced MDA levels, enhanced GSH-Px activity, and reduced glomerular pathological changes [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Renal Protective Effect of Probucol in Rats with Contrast-Induced Nephropathy and its Underlying Mechanism

Wang

Wei

et al. 2015

Med Sci Monit

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BackgroundContrast-induced nephropathy (CIN) refers to acute renal damage that occurs after the use of contrast agents. This study investigated the renal protective effect of probucol in a rat model of contrast-induced nephropathy and the mechanism of its effect.Material/MethodsTwenty-eight Wistar rats were randomly divided into the control group, model group, N-acetylcysteine(NAC) group, and probucol group. We used a rat model of iopromide-induced CIN. One day prior to modeling, the rats received gavage. At 24 h after the modeling, blood biochemistry and urine protein were assessed. Malondialdehyde (MDA) and superoxide dismutase (SOD) were measured in renal tissue. Kidney sections were created for histopathological examination.ResultsThe model group of rats showed significantly elevated levels of blood creatinine, urea nitrogen, 24-h urine protein, histopathological scores, and parameters of oxidative stress (P<0.05). Both the NAC and probucol groups demonstrated significantly lower Scr, BUN, and urine protein levels compared to the model group (P<0.05), with no significant difference between these 2 groups. The NAC group and the probucol group had significantly lower MDA and higher SOD than the model group at 24 h after modeling (P<0.05). The 8-OHdG-positive tubule of the probucol group and NAC group were significantly lower than those of the model group (p=0.046, P=0.0008), with significant difference between these 2 groups (P=0.024).ConclusionsProbucol can effectively reduce kidney damage caused by contrast agent. The underlying mechanism may be that probucol accelerates the recovery of renal function and renal pathology by reducing local renal oxidative stress.

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Section: Discussionmentioning

confidence: 99%

Renal Protective Effect of Probucol in Rats with Contrast-Induced Nephropathy and its Underlying Mechanism

Wang

Wei

et al. 2015

Med Sci Monit

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“…ROS are also able to inhibit LKB1-mediated activation of AMPK, alleviating mTOR inhibition and promoting entry into the cell-cycle and glioma proliferation in vitro (Jiang et al, 2014). Downstream of AMPK, PGC-1α controls transcription of antioxidative proteins alongside mitochondrial biogenesis, highlighting the tight control of ROS in response to increased mitochondrial respiration (Hartel et al, 2016).…”

Section: Reactive Oxygen Species and Redox Homeostasismentioning

confidence: 99%

“…Mutations in the tumor suppressor LKB1 limit AMPK activity and the production of NADPH through catabolic processes; unrestrained ROS can promote tumor growth by boosting oncogenic signal transduction, genetic instability and glioma growth in vivo (Jeon et al, 2012 ). ROS are also able to inhibit LKB1-mediated activation of AMPK, alleviating mTOR inhibition and promoting entry into the cell-cycle and glioma proliferation in vitro (Jiang et al, 2014 ). Downstream of AMPK, PGC-1α controls transcription of antioxidative proteins alongside mitochondrial biogenesis, highlighting the tight control of ROS in response to increased mitochondrial respiration (Hartel et al, 2016 ).…”

Section: Reactive Oxygen Species and Redox Homeostasismentioning

confidence: 99%

Metabolic Reprogramming in Glioma

Strickland

Stoll

2017

Front. Cell Dev. Biol.

266

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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“…AMP-activated protein kinase (AMPK) is a key regulator of energy metabolism [ 7 ] by activating the synthesis of fatty acid, cholesterol, protein through phosphorylation of metabolic enzymes and ATP-generating processes, including glucose uptake [ 8 ]. A tumor suppressor liver kinase B1 (LKB1) is its upstream kinase that phosphorylates and activates AMPK signaling by encoding serine/threonine kinase [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Reactive oxygen species dependent phosphorylation of the liver kinase B1/AMP activated protein kinase/ acetyl-CoA carboxylase signaling is critically involved in apoptotic effect of lambertianic acid in hepatocellular carcinoma cells

et al. 2017

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Though lambertianic acid (LA) is reported to have hypolipidemic activity in liver, its underlying anticancer mechanism is poorly understood so far. Thus, in the present study, apoptotic mechanism of LA was elucidated in HepG2 and SK-Hep1 hepatocellular carcinoma (HCC) cells. Here LA increased cytotoxicity, sub-G1 population and Annexin V/PI positive cells in two HCC cells. Also, LA cleaved caspase-3 and poly(ADP-ribose) polymerase (PARP), activated phosphorylation of liver kinase B1 (LKB1)/AMP activated protein kinase (AMPK)/ acetyl-CoA carboxylase (ACC) pathway and also suppressed antiapoptotic proteins such as phosphorylation of Akt/ mammalian target of rapamycin (mTOR) and the expression of B cell lymphoma-2 (Bcl-2)/ B-cell lymphoma-extra large (Bcl-xL) and cyclooxygenase-2 (COX-2) in two HCC cells. Furthermore, LA generated reactive oxygen species (ROS) in HepG2 cells and AMPK inhibitor compound C or ROS inhibitor N-acetyl-L-cysteine (NAC) blocked the apoptotic ability of LA to cleave PARP or increase sub G1 population in HepG2 cells. Consistently, cleavages of PARP and caspase-3 were induced by LA only in AMPK+/+ MEF cells, but not in AMPK-/- MEF cells. Also, immunoprecipitation (IP) revealed that phosphorylation of LKB1/AMPK through their binding was enhanced in LA treated HepG2 cells. Overall, these findings suggest that ROS dependent phosphorylation of LKB1/AMPK/ACC signaling is critically involved in LA induced apoptosis in HCCs.

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Probucol suppresses human glioma cell proliferation in vitro via ROS production and LKB1-AMPK activation

Cited by 9 publications

References 29 publications

Renal Protective Effect of Probucol in Rats with Contrast-Induced Nephropathy and its Underlying Mechanism

Renal Protective Effect of Probucol in Rats with Contrast-Induced Nephropathy and its Underlying Mechanism

Metabolic Reprogramming in Glioma

Reactive oxygen species dependent phosphorylation of the liver kinase B1/AMP activated protein kinase/ acetyl-CoA carboxylase signaling is critically involved in apoptotic effect of lambertianic acid in hepatocellular carcinoma cells

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