scholarly journals Aurora kinase A inhibition reverses the Warburg effect and elicits unique metabolic vulnerabilities in glioblastoma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Trang T. T. Nguyen ◽  
Enyuan Shang ◽  
Chang Shu ◽  
Sungsoo Kim ◽  
Angeliki Mela ◽  
...  
Keyword(s):  
Aurora Kinase ◽  
Critical Issue ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Novel Therapy ◽  
Peroxisome Proliferator Activated Receptor ◽  
Aurora Kinase A ◽  
Extracellular Flux ◽  
Kinase A

AbstractAurora kinase A (AURKA) has emerged as a drug target for glioblastoma (GBM). However, resistance to therapy remains a critical issue. By integration of transcriptome, chromatin immunoprecipitation sequencing (CHIP-seq), Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq), proteomic and metabolite screening followed by carbon tracing and extracellular flux analyses we show that genetic and pharmacological AURKA inhibition elicits metabolic reprogramming mediated by inhibition of MYC targets and concomitant activation of Peroxisome Proliferator Activated Receptor Alpha (PPARA) signaling. While glycolysis is suppressed by AURKA inhibition, we note an increase in the oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO), which was accompanied by an increase of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). Combining AURKA inhibitors with inhibitors of FAO extends overall survival in orthotopic GBM PDX models. Taken together, these data suggest that simultaneous targeting of oxidative metabolism and AURKAi might be a potential novel therapy against recalcitrant malignancies.

scholarly journals TAMI-33. AURKA INHIBITION REPROGRAMS METABOLISM AND IS SYNTHETICALLY LETHAL WITH FATTY ACID OXIDATION INHIBITION IN GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii220-ii220
Author(s):  
Trang Nguyen ◽  
Enyuan Shang ◽  
Chang Shu ◽  
Angeliki Mela ◽  
Nelson Humala ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Oxidative Metabolism ◽  
Aurora Kinase ◽  
Critical Issue ◽  
Primary Brain Tumor ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Flux Analysis ◽  
Novel Therapy

Abstract Aurora kinase A (AURKA) has emerged as a viable drug target for glioblastoma (GBM), the most common malignant primary brain tumor in adults with a life expectancy of 12-15 months. However, resistance to therapy remains a critical issue, which partially may be driven by reprogramming of metabolism. By integration of transcriptome, chromatin immunoprecipitation with sequencing (CHIP-seq.), assay for transposase-accessible chromatin with sequencing (ATAC-seq.), proteomic and metabolite screening followed by carbon tracing (U-13C-Glucose, U-13C-Glutamine and U-13C-Palmitic acid) and extracellular flux analysis we provided evidence that genetic (shRNA and CRISPR/Cas9) and pharmacological (Alisertib) AURKA inhibition elicited substantial metabolic reprogramming mediated in part by inhibition of MYC targets and concomitant activation of PPARA (e.g. PGC1A) signaling. While glycolysis was suppressed by AURKA inhibition, we noted a compensatory increase in oxygen consumption rate (OCR) fueled by fatty acid oxidation (FAO). Whereas interference with AURKA elicited a suppression of c-Myc, we detected an upregulation of PGC1A, a master regulator of oxidative metabolism, upon AURKA inhibition. Silencing of PGC1A reversed the increase in OCR and sensitized GBM cells to AURKA inhibition mediated reduction in cellular viability. CHIP experiments confirmed binding of c-Myc to the promoter region of PGC1A, which is abrogated by AURKA inhibition and in turn unleashed PGC1A expression. ATAC-seq. confirmed higher accessibility of the MYC binding region within the PGC1A promoter. Forced expression of c-Myc blocked AURKA inhibition mediated increase of PGC1A, suggesting that c-Myc acted as a repressor. To interfere with this oxidative metabolic reprogramming, we combined AURKA inhibitors with blockers of FAO (etomoxir), which elicited substantial synergistic growth inhibition and extension of overall survival in orthotopic patient derived xenografts of GBM in mice without induction of toxicity in normal tissue. Taken together, these data support that simultaneous targeting of oxidative metabolism and AURKA inhibition might be a potential novel therapy against GBM.

scholarly journals MiR-9-5p protects from kidney fibrosis by metabolic reprogramming

2019 ◽  
Author(s):  
Marta Fierro-Fernández ◽  
Verónica Miguel ◽  
Laura Márquez-Expósito ◽  
Cristina Nuevo-Tapioles ◽  
J. Ignacio Herrero ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Metabolic Derangement ◽  
Peroxisome Proliferator Activated Receptor ◽  
Kidney Fibrosis ◽  
Tgf Β1

AbstractMicroRNAs (miRNAs) regulate gene expression post-transcriptionally and control biological processes, including fibrogenesis. Kidney fibrosis remains a clinical challenge and miRNAs may represent a valid therapeutic avenue. We show that miR-9-5p protected from renal fibrosis in the mouse model of unilateral ureteral obstruction (UUO). This was reflected in reduced expression of pro-fibrotic markers, decreased number of infiltrating monocytes/macrophages and diminished tubular epithelial cell injury and transforming growth factor-beta 1 (TGF-β1)-dependent de-differentiation in human kidney proximal tubular (HKC-8) cells. RNA sequencing (RNA-Seq) studies in the UUO model revealed that this protection was mediated by a global shift in the expression profile of genes related to key metabolic pathways, including mitochondrial dysfunction, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO) and glycolysis, preventing their UUO-dependent down-regulation. This effect was mirrored by a prevention in the TGF-β1-induced bioenergetics changes in HKC-8 cells. The expression of the FAO-related axis peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α)-peroxisome proliferator-activated receptor alpha (PPARα) was reduced by UUO, although preserved by the administration of miR-9-5p. We found that in mice null for the mitochondrial master regulator PGC-1α, miR-9-5p was unable to promote a protective effect in the UUO model. We propose that miR-9-5p elicits a protective response to chronic kidney injury and renal fibrosis by inducing reprogramming of the metabolic derangement and mitochondrial dysfunction affecting tubular epithelial cells.

Die Expression der Aurora Kinase A korreliert mit dem Wnt-Modulator RACGAP1 im Magenkarzinom

2015 ◽  
Vol 53 (08) ◽  
Author(s):  
J Bornschein ◽  
J Nielitz ◽  
I Drozdov ◽  
M Selgrad ◽  
T Wex ◽  
...  
Keyword(s):  
Aurora Kinase ◽  
Aurora Kinase A ◽  
Kinase A

Natural Aldose Reductase Inhibitor: A Potential Therapeutic Agent for Non-alcoholic Fatty Liver Disease

2020 ◽  
Vol 21 (6) ◽  
pp. 599-609 ◽  
Author(s):  
Longxin Qiu ◽  
Chang Guo
Keyword(s):  
Oxidative Stress ◽  
Liver Disease ◽  
Fatty Liver ◽  
Aldose Reductase ◽  
Fatty Liver Disease ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alcoholic Fatty Liver ◽  
Nonalcoholic Fatty Liver

Aldose reductase (AR) has been reported to be involved in the development of nonalcoholic fatty liver disease (NAFLD). Hepatic AR is induced under hyperglycemia condition and converts excess glucose to lipogenic fructose, which contributes in part to the accumulation of fat in the liver cells of diabetes rodents. In addition, the hyperglycemia-induced AR or nutrition-induced AR causes suppression of the transcriptional activity of peroxisome proliferator-activated receptor (PPAR) α and reduced lipolysis in the liver, which also contribute to the development of NAFLD. Moreover, AR induction in non-alcoholic steatohepatitis (NASH) may aggravate oxidative stress and the expression of inflammatory cytokines in the liver. Here, we summarize the knowledge on AR inhibitors of plant origin and review the effect of some plant-derived AR inhibitors on NAFLD/NASH in rodents. Natural AR inhibitors may improve NAFLD at least in part through attenuating oxidative stress and inflammatory cytokine expression. Some of the natural AR inhibitors have been reported to attenuate hepatic steatosis through the regulation of PPARα-mediated fatty acid oxidation. In this review, we propose that the natural AR inhibitors are potential therapeutic agents for NAFLD.

scholarly journals Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
KyeongJin Kim ◽  
Jin Ku Kang ◽  
Young Hoon Jung ◽  
Sang Bae Lee ◽  
Raffaela Rametta ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Whole Body ◽  
Acid Oxidation ◽  
Chow Diet ◽  
Peroxisome Proliferator ◽  
Obese Mice ◽  
Ph Domain ◽  
Peroxisome Proliferator Activated Receptor

AbstractIncreased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.

scholarly journals Targeting Aurora kinase A and JAK2 prevents GVHD while maintaining Tregand antitumor CTL function

2017 ◽  
Vol 9 (372) ◽  
pp. eaai8269 ◽  
Author(s):  
Brian C. Betts ◽  
Anandharaman Veerapathran ◽  
Joseph Pidala ◽  
Hua Yang ◽  
Pedro Horna ◽  
...  
Keyword(s):  
Aurora Kinase ◽  
Aurora Kinase A ◽  
Kinase A

scholarly journals Protein Kinase A/CREB Signaling Prevents Adriamycin-Induced Podocyte Apoptosis via Upregulation of Mitochondrial Respiratory Chain Complexes

2017 ◽  
Vol 38 (1) ◽  
Author(s):  
Kewei Xie ◽  
Mingli Zhu ◽  
Peng Xiang ◽  
Xiaohuan Chen ◽  
Ayijiaken Kasimumali ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Respiratory Chain ◽  
Mitochondrial Respiratory Chain ◽  
Peroxisome Proliferator ◽  
Respiratory Chain Complexes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Kinase A ◽  
Mitochondrial Respiratory

ABSTRACT Previous work showed that the activation of protein kinase A (PKA) signaling promoted mitochondrial fusion and prevented podocyte apoptosis. The cAMP response element binding protein (CREB) is the main downstream transcription factor of PKA signaling. Here we show that the PKA agonist 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate–cyclic AMP (pCPT-cAMP) prevented the production of adriamycin (ADR)-induced reactive oxygen species and apoptosis in podocytes, which were inhibited by CREB RNA interference (RNAi). The activation of PKA enhanced mitochondrial function and prevented the ADR-induced decrease of mitochondrial respiratory chain complex I subunits, NADH-ubiquinone oxidoreductase complex (ND) 1/3/4 genes, and protein expression. Inhibition of CREB expression alleviated pCPT-cAMP-induced ND3, but not the recovery of ND1/4 protein, in ADR-treated podocytes. In addition, CREB RNAi blocked the pCPT-cAMP-induced increase in ATP and the expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1-α). The chromatin immunoprecipitation assay showed enrichment of CREB on PGC1-α and ND3 promoters, suggesting that these promoters are CREB targets. In vivo, both an endogenous cAMP activator (isoproterenol) and pCPT-cAMP decreased the albumin/creatinine ratio in mice with ADR nephropathy, reduced glomerular oxidative stress, and retained Wilm's tumor suppressor gene 1 (WT-1)-positive cells in glomeruli. We conclude that the upregulation of mitochondrial respiratory chain proteins played a partial role in the protection of PKA/CREB signaling.

Inhibition of Aurora Kinase A enhances chemosensitivity of medulloblastoma cell lines

2010 ◽  
Vol 55 (1) ◽  
pp. 35-41 ◽  
Author(s):  
Ayman El-Sheikh ◽  
Rong Fan ◽  
Diane Birks ◽  
Andrew Donson ◽  
Nicholas K Foreman ◽  
...  
Keyword(s):  
Cell Lines ◽  
Aurora Kinase ◽  
Aurora Kinase A ◽  
Medulloblastoma Cell ◽  
Kinase A ◽  
Medulloblastoma Cell Lines
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