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pepck-m recoups tumor cell anabolic potential in a PKC-ζ-dependent manner

CANCER & mETABOLISm 2021年第1期9卷 1页

作者： Hyrossova, Petra Arago, marc moreno-Felici, Juan Fu, Xiarong mendez-Lucas, Andres Garcia-Roves, Pablo m. Burgess, Shawn Figueras, Agnes Vinals, Francesc Perales, Jose C. Univ Barcelona Sch Med Dept Physiol Sci Feixa Llarga S-N Lhospitalet De Llobregat 08907 Spain Univ Texas Dallas Ctr Human Nutr Dallas TX 75390 USA Univ Texas Dallas Dept Pharmacol Dallas TX 75390 USA IDIBELL Gran Via Hospitalet 199 Lhospitalet De Llobregat 08908 Spain

Background: mitochondrial phosphoenolpyruvate carboxykinase (pepck-m;PCK2) is expressed in all cancer types examined and in neuroprogenitor cells. The gene is upregulated by amino acid limitation and ER-stress in an ATF4-dependent manner, and its activity modulates the PEP/Ca2+ signaling axis, providing clear arguments for a functional relationship with metabolic adaptations for cell survival. Despite its potential relevance to cancer metabolism, the mechanisms responsible for its pro-survival activity have not been completely elucidated. methods: [U-C-13]glutamine and [U-C-13]glucose labeling of glycolytic and TCA cycle intermediates and their anabolic end-products was evaluated quantitatively using LC/mS and GC/mS in conditions of abundant glucose and glucose limitation in loss-of-function (shRNA) and gain-of-function (lentiviral constitutive overexpression) HeLa cervix carcinoma cell models. Cell viability was assessed in conjunction with various glucose concentrations and in xenografts in vivo. Results: pepck-m levels linearly correlated with [U-C-13]glutamine label abundance in most glycolytic and TCA cycle intermediate pools under nutritional stress. In particular, serine, glycine, and proline metabolism, and the anabolic potential of the cell, were sensitive to pepck-m activity. Therefore, cell viability defects could be rescued by supplementing with an excess of those amino acids. pepck-m silenced or inhibited cells in the presence of abundant glucose showed limited growth secondary to TCA cycle blockade and increased ROS. In limiting glucose conditions, downregulation of PKC-zeta tumor suppressor has been shown to enhance survival. Consistently, HeLa cells also sustained a survival advantage when PKC-zeta tumor suppressor was downregulated using shRNA, but this advantage was abolished in the absence of pepck-m, as its inhibition restores cell growth to control levels. The relationship between these two pathways is also highlighted by the anti-correlation ob

关键词： pepck pepck-m PCK2 Phosphoenolpyruvate carboxykinase Cancer metabolism PEP Phosphoenolpyruvate ER stress Amino acid deprivation PKC-zeta ATF4 Activating transcription factor 4 AAR Amino acid response GCN2 TCA cycle Cataplerosis Serine/glycine metabolism Proline metabolism PYCR PRODH/POX

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mitochondrial Phosphoenolpyruvate Carboxykinase (pepck-m) Is a Pro-survival, Endoplasmic Reticulum (ER) Stress Response Gene Involved in Tumor Cell Adaptation to Nutrient Availability

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JOURNAL OF BIOLOGICAL CHEmISTRY 2014年第32期289卷 22090-22102页

作者： mendez-Lucas, Andres Hyrossova, Petra Novellasdemunt, Laura Vinals, Francesc Perales, Jose C. Univ Barcelona Dept Ciencies Fisiol 2 E-08907 Barcelona Spain

mitochondrial phosphoenolpyruvate carboxykinase (pepck-m), encoded by the nuclear PCK2 gene, links TCA cycle intermediates and glycolytic pools through the conversion of mitochondrial oxaloacetate into phosphoenolpyruvate. In the liver pepck-m adjoins its profusely studied cytosolic isoform (pepck-C) potentiating gluconeogenesis and TCA flux. However, pepck-m is present in a variety of non-gluconeogenic tissues, including tumors of several origins. Despite its potential relevance to cancer metabolism, the mechanisms responsible for PCK2 gene regulation have not been elucidated. The present study demonstrates pepck-m overexpression in tumorigenic cells as well as the mechanism for the modulation of PCK2 abundance under several stress conditions. Amino acid limitation and ER stress inducers, conditions that activate the amino acid response (AAR) and the unfolded protein response (UPR), stimulate PCK2 gene transcription. Both the AAR and UPR lead to increased synthesis of ATF4, which mediates PCK2 transcriptional up-regulation through its binding to a putative ATF/CRE composite site within the PCK2 promoter functioning as an amino acid response element. In addition, activation of the GCN2-eIF2 alpha-ATF4 and PERK-eIF2 alpha-ATF4 signaling pathways are responsible for increased pepck-m levels. Finally, pepck-m knockdown using either siRNA or shRNA were sufficient to reduce mCF7 mammary carcinoma cell growth and increase cell death under glutamine deprivation or ER stress conditions. Our data demonstrate that this enzyme has a critical role in the survival program initiated upon stress and shed light on an unexpected and important role of mitochondrial pepck in cancer metabolism.

关键词： AAR AARE ATF4 Cell metabolism ER Stress pepck-m Transcription Regulation Tumor metabolism UPR Unfolded Protein Response (UPR)

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Neuronal Progenitor maintenance Requires Lactate metabolism and pepck-m-Directed Cataplerosis

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CEREBRAL CORTEX 2016年第3期26卷 1046-1058页

作者： Alvarez, Zaida Hyrossova, Petra Carlos Perales, Jose Alcantara, Soledad IBEC Inst Bioengn Catalonia Barcelona Spain Univ Barcelona Sch Med Dept Pathol & Expt Therapeut Bellvitge Campus Barcelona Spain Univ Barcelona Sch Med Dept Physiol Sci 2 Bellvitge Campus Barcelona Spain CIBER Bioingn Biomat Nanomed CIBER BBN Barcelona Spain

This study investigated the metabolic requirements for neuronal progenitor maintenance in vitro and in vivo by examining the metabolic adaptations that support neuronal progenitors and neural stem cells (NSCs) in their undifferentiated state. We demonstrate that neuronal progenitors are strictly dependent on lactate metabolism, while glucose induces their neuronal differentiation. Lactate signaling is not by itself capable of maintaining the progenitor phenotype. The consequences of lactate metabolism include increased mitochondrial and oxidative metabolism, with a strict reliance on cataplerosis through the mitochondrial phosphoenolpyruvate carboxykinase (pepck-m) pathway to support anabolic functions, such as the production of extracellular matrix. In vivo, lactate maintains/induces populations of postnatal neuronal progenitors/NSCs in a pepck-m-dependent manner. Taken together, our data demonstrate that, lactate alone or together with other physical/biochemical cues maintain NSCs/progenitors with a metabolic signature that is classically found in tissues with high anabolic capacity.

关键词： lactate metabolism neural progenitors neurons pepck-m

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Pharmacology and preclinical validation of a novel anticancer compound targeting pepck-m

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BIOmEDICINE & PHARmACOTHERAPY 2020年 121卷 109601-000页

作者： Arago, marc moreno-Felici, Juan Abas, Sonia Rodriguez-Arevalo, Sergio Hyrossova, Petra Figueras, Agnes Vinals, Francesc Perez, Belen Loza, maria, I Brea, Jose Latorre, Pedro Carrodeguas, Jose A. Garcia-Roves, Pablo m. Galdeano, Carlos Ginex, Tiziana Luque, Francisco J. Escolano, Carmen Perales, Jose C. Univ Barcelona Sch Med Dept Physiol Sci Lhospitalet De Llobregat Spain Univ Barcelona Fac Pharm & Food Sci Lab Med ChemAssociated Unit CSIC Barcelona Spain Univ Barcelona Inst Biomed IBUB Barcelona Spain Bellvitge Inst Biomed Res IDIBELL Catalan Inst Oncol Program Mol Mech & Expt Therapeut Oncol ONCOBell Lhospitalet De Llobregat Spain Bellvitge Inst Biomed Res IDIBELL Catalan Inst Oncol Program Canc Therapeut Resistance ProCURE Lhospitalet De Llobregat Spain Autonomous Univ Barcelona Dept Pharmacol Therapeut & Toxicol Bellaterra Spain Univ Santiago de Compostela Ctr Invest Med Mol & Enfermedades Cron CIMUS BioFarma Res Grp Innopharma Screening Platform Santiago De Compostela Spain Univ Zaragoza Fac Ciencias Inst Biocomp & Fis Sistemas Complejos BIFI Dept Bioquim & Biol Mol & CelularIQFRCSIC Zaragoza Spain Univ Barcelona Sch Pharm Dept Pharm Pharmaceut Technol & Phys Chem Barcelona Spain Univ Barcelona Sch Pharm & Food Sci Inst Biomed IBUB Dept Nutr Food Sci & Gastron Santa Coloma de Gramenet Spain Univ Barcelona Inst Theoret & Computat Chem IQTCUB Santa Coloma de Gramenet Spain

Background: Phosphoenolpyruvate carboxykinase (pepck) catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate. The mitochondrial isozyme, pepck-m is highly expressed in cancer cells, where it plays a role in nutrient stress response. To date, pharmacological strategies to target this pathway have not been pursued. methods: A compound embodying a 3-alkyl-1,8-dibenzylxanthine nucleus (ipepck-2), was synthesized and successfully probed in silico on a pepck-m structural model. Potency and target engagement in vitro and in vivo were evaluated by kinetic and cellular thermal shift assays (CETSA). The compound and its target were validated in tumor growth models in vitro and in murine xenografts. Results: Cross-inhibitory capacity and increased potency as compared to 3-mPA were confirmed in vitro and in vivo. Treatment with ipepck-2 inhibited cell growth and survival, especially in poor-nutrient environment, consistent with an impact on colony formation in soft agar. Finally, daily administration of the pepck-m inhibitor successfully inhibited tumor growth in two murine xenograft models as compared to vehicle, without weight loss, or any sign of apparent toxicity. Conclusion: We conclude that ipepck-2 is a compelling anticancer drug targeting pepck-m, a hallmark gene product involved in metabolic adaptations of the tumor.

关键词： pepck-m Xanthine derivatives pepck inhibitors Cancer metabolism Xenograft Gluconeogenesis Breast carcinoma Colon carcinoma Preclinical mitochondrial physiology CETSA Insulin secretion

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The mitochondrial isoform of phosphoenolpyruvate carboxykinase (pepck-m) and glucose homeostasis: Has it been overlooked?

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BIOCHImICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS 2014年第4期1840卷 1313-1330页

作者： Stark, Romana Kibbey, Richard G. Monash Univ Dept Physiol Clayton Vic 3800 Australia Yale Univ Sch Med Dept Internal Med New Haven CT 06520 USA

Background: Plasma glucose levels are tightly regulated within a narrow physiologic range. Insulin-mediated glucose uptake by tissues must be balanced by the appearance of glucose from nutritional sources, glycogen stores, or gluconeogenesis. In this regard, a common pathway regulating both glucose clearance and appearance has not been described. The metabolism of glucose to produce ATP is generally considered to be the primary stimulus for insulin release from beta-cells. Similarly, gluconeogenesis from phosphoenolpyruvate (PEP) is believed to be the primarily pathway via the cytosolic isoform of phosphoenolpyruvate carboxykinase (pepck-C). These models cannot adequately explain the regulation of insulin secretion or gluconeogenesis. Scope of review: A metabolic sensing pathway involving mitochondrial GTP (mtGTP) and PEP synthesis by the mitochondrial isoform of pepck (pepck-m) is associated with glucose-stimulated insulin secretion from pancreatic beta-cells. Here we examine whether there is evidence for a similar mtGTP-dependent pathway involved in gluconeogenesis. In both islets and the liver, mtGTP is produced at the substrate level by the enzyme succinyl CoA synthetase (SCS-GTP) with a rate proportional to the TCA cycle. In the beta-cell pepck-m then hydrolyzes mtGTP in the production of PEP that, unlike mtGTP, can escape the mitochondria to generate a signal for insulin release. Similarly, pepck-m and mtGTP might also provide a significant source of PEP in gluconeogenic tissues for the production of glucose. This review will focus on the possibility that pepck-m, as a sensor for TCA cycle flux, is a key mechanism to regulate both insulin secretion and gluconeogenesis suggesting conservation of this biochemical mechanism in regulating multiple aspects of glucose homeostasis. moreover, we propose that this mechanism may be important for regulating insulin secretion and gluconeogenesis compared to canonical nutrient sensing pathways. major conclusions: pepck-m,

关键词： pepck-m mitochondrial GTP Anaplerosis Succinyl coenzyme A synthetase Insulin secretion Gluconeogenesis

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Computational evaluation of natural compounds as potential inhibitors of human pepck-m: An alternative for lung cancer therapy

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Advances and Applications in Bioinformatics and Chemistry 2019年 12卷 15-32页

作者： Baptista, Luiz Phillippe R. Sinatti, Vanessa V. C. da Silva, Joao H. m. Dardenne, Laurent Emmanuel Guimarães, Ana Carolina Laboratory for Functional Genomics and Bioinformatics Fiocruz Oswaldo Cruz Institute Rio de Janeiro RJ Brazil Group for Computational Modelling Fiocruz Oswaldo Cruz Foundation Eusébio CE Brazil Group for Molecular Modelling of Biologic Systems National Laboratory of Scientific Computing Petrópolis RJ Brazil

Background: Lung cancer is the leading cause of cancer-related death worldwide. Among its subtypes, non-small cell lung cancer (NSCLC) is the most common. Recently, the mitochondrial isoform of the enzyme phosphoenolpyruvate carboxykinase (Hspepck-m) was identified as responsible for the metabolic adaptation in the NSCLC allowing tumor growth even under conditions of glucose deficiency. This adaptation is possible due to the role of Hspepck-m in gluconeogenesis, converting the oxaloacetate to phosphoenolpyruvate in the presence of GTP, which plays an important role in the energetic support of these tumors. In this context, it was shown that the inhibition or knockdown of this enzyme was able to induce apoptosis in NSCLC under low glucose conditions. Purpose: In this study, novel putative inhibitors were proposed for the human pepck-m (Hspepck-m) based on a computer-aided approach. methods: Comparative modeling was used to generate 3D models for Hspepck-m. Subsequently, the set of natural compounds of the ZINC database was screened against Hspepck-m models using structure-based pharmacophore modeling and molecular docking approaches. The selected compounds were evaluated according to its chemical diversity and clustered based on chemical similarity. Results: The pharmacophore hypotheses, generated based on known pepck inhibitors, were able to select 7,124 candidate compounds. These compounds were submitted to molecular docking studies using three conformations of Hspepck-m generated by comparative modeling. The aim was to select compounds with high predicted binding affinity for at least one of the conformations of Hspepck-m. After molecular docking, 612 molecules were selected as potential inhibitors of Hspepck-m. These compounds were clustered according to their structural similarity. Chemical profiling and binding mode analyses of these compounds allowed the proposal of four promising compounds: ZINC01656421, ZINC895296, ZINC00895535 and ZINC02571340. Conclusion:

关键词： Lung cancer molecular docking Natural products pepck-m Pharmacophore modeling Virtual screening

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Phosphoenolpyruvate carboxykinase is involved in antiviral immunity against Bombyx mori nucleopolyhedrovirus

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DEVELOPmENTAL AND COmPARATIVE ImmUNOLOGY 2019年 92卷 193-198页

作者： Guo, Huizhen Xu, Guowen Wang, Bingbing Xia, Fei Sun, Qiang Wang, Yumei Xie, Enyu Lu, Zhongyan Jiang, Liang Xia, Qingyou Southwest Univ State Key Lab Silkworm Genome Biol Chongqing 400715 Peoples R China Southwest Univ Chongqing Engn & Technol Res Ctr Novel Silk Mat Chongqing Key Lab Sericultural Sci Chongqing 400715 Peoples R China

Phosphoenolpyruvate carboxykinase (pepck) has cytoplasmic isoform (pepck-C) and a mitochondrial isoform (pepck-m). pepck-C plays an important role in gluconeogenesis, but the function of pepck-m is largely unknown. In this study, we cloned two isoforms of pepck (Bmpepck-1 and Bmpepck-2;both of pepck-m) from the lepidopteran model Bombyx mori. Bmpepck-1 and Bmpepck-2 were adjacently located in the silkworm genome, and both contained 13 exons. The main difference in the sequences was the 13th exon and 3'UTR. The expression of Bmpepck-1 was higher than that of Bmpepck-2, the overexpression of which did not affect BmNPV proliferation. The expression levels of Bmpepck-2 and ATG6/7/8/13 decreased after BmNPV infection. Overexpression of Bmpepck-2 increased the expression of ATG6/7/8 and significantly decreased viral fluorescence and content, suggesting that Bmpepck-2 suppressed the multiplication of BmNPV by increasing ATGs expression. These results revealed that pepck-m has an important function in antiviral immunity.

关键词： pepck-m Silkworm BmNPV Antiviral ATGs

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mitochondrial GTP Links Nutrient Sensing to β Cell Health, mitochondrial morphology, and Insulin Secretion Independent of OxPhos

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CELL REPORTS 2019年第3期28卷 759-+页

作者： Jesinkey, Sean R. madiraju, Anila K. Alves, Tiago C. Yarborough, OrLando H. Cardone, Rebecca L. Zhao, Xiaojian Parsaei, Yassmin Nasiri, Ali R. Butrico, Gina Liu, Xinran molina, Anthony J. Rountree, Austin m. Neal, Adam S. Wolf, Dane m. Sterpka, John Philbrick, William m. Sweet, Ian R. Shirihai, Orian H. Kibbey, Richard G. Yale Univ Sch Med Dept Internal Med New Haven CT 06519 USA Yale Univ Sch Med Dept Cellular & Mol Physiol New Haven CT 06519 USA Yale Univ Sch Med Dept Cell Biol New Haven CT 06519 USA Univ Calif San Diego Dept Med Div Geriatr & Gerontol La Jolla CA 92093 USA Boston Univ Sch Med Dept Med Boston MA 02118 USA Univ Washington Dept Med Diabet Inst Seattle WA 98195 USA Univ Calif Los Angeles David Geffen Sch Med Dept Med Los Angeles CA 90095 USA Univ Calif Los Angeles David Geffen Sch Med Dept Endocrinol Los Angeles CA 90095 USA Univ Calif Los Angeles David Geffen Sch Med Dept Mol & Med Pharmacol Los Angeles CA 90095 USA

mechanisms coordinating pancreatic beta cell metabolism with insulin secretion are essential for glucose homeostasis. One key mechanism of beta cell nutrient sensing uses the mitochondrial GTP (mtGTP) cycle. In this cycle, mtGTP synthesized by succinyl-CoA synthetase (SCS) is hydrolyzed via mitochondrial pepck (pepck-m) to make phosphoenolpyruvate, a high-energy metabolite that integrates TCA cycling and anaplerosis with glucose-stimulated insulin secretion (GSIS). Several strategies, including xeno-topic overexpression of yeast mitochondrial GTP/GDP exchanger (GGC1) and human ATP and GTP-specific SCS isoforms, demonstrated the importance of the mtGTP cycle. These studies confirmed that mtGTP triggers and amplifies normal GSIS and rescues defects in GSIS both in vitro and in vivo. Increased mtGTP synthesis enhanced calcium oscillations during GSIS. mtGTP also augmented mitochondrial mass, increased insulin granule number, and membrane proximity without triggering de-differentiation or metabolic fragility. These data highlight the importance of the mtGTP signal in nutrient sensing, insulin secretion, mitochondrial maintenance, and beta cell health.

关键词： mitochondrial GTP pepck-m insulin secretion oxidative phosphorylation phosphoenolpyruvate anaplerosis succinyl-CoA synthetase stable isotope metabolic flux mImOSA

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鸡胚胎期磷酸烯醇式丙酮酸羧激酶和丙酮酸羧化酶mRNA含量的变化规律

鸡胚胎期磷酸烯醇式丙酮酸羧激酶和丙酮酸羧化酶mRNA含量的变化规...

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作者：满斗日花内蒙古农业大学

学位级别：硕士

在白色莱航鸡孵化第13d～21d期间,每天随机选取7-8个胚胎,从中再随机选取5个胚胎,并分别采集肝脏、肾脏和骨骼肌样品(n=5),分离出各组织中的总RNA,根据GenBank中PC和pepck的基因序列,用Primer Express2.0及Primer3设计并合成一对引物,... 详细信息

在白色莱航鸡孵化第13d～21d期间,每天随机选取7-8个胚胎,从中再随机选取5个胚胎,并分别采集肝脏、肾脏和骨骼肌样品(n=5),分离出各组织中的总RNA,根据GenBank中PC和pepck的基因序列,用Primer Express2.0及Primer3设计并合成一对引物,分别对其肝脏、肾脏和骨骼肌中丙酮酸羧化酶(PC)、线粒体型磷酸烯醇式丙酮酸羧激酶(pepck-m)和细胞型磷酸烯醇式丙酮酸羧激酶(pepck-C)的mRNA进行实时荧光定量PCR(RT-PCR)分析,并应用核酸序列分析法对其进行同源性分析和鉴定目的片段,旨在了解鸡胚胎发育过程中糖异生作用的三种关键酶的mRNA表达规律。结果表明: (1)孵化第13d、15d、17d、19d和21d的胚胎和成年鸡的PC mRNA在肝脏中的表达量相对高于在肾脏和骨骼肌中的表达量;pepck-C mRNA在肾脏中的表达量相对高于肝脏和骨骼肌中的表达量;pepck-m mRNA在肝脏中的表达量相对高于肾脏和骨骼肌中的表达量;但差异均不显著(p>0.05),孵化期胚胎肝脏中PC mRNA含量显著高于成年鸡的PC mRNA含量(p<0.05)。孵化第21d pepck-C mRNA表达量显著高于孵化第13d和第15d的pepck-C mRNA表达量(p<0.05);孵化第15d肝脏中pepck-m mRNA表达量显著高于孵化第21d和成年鸡pepck-m mRNA的表达量(p<0.05)。 (2)孵化偶数日第14d、16d、18d和20d胚胎的PC mRNA在肝脏中的表达量相对高于肾脏和骨骼肌中的表达量;pepck-C mRNA在肾脏中的表达量相对高于肝脏和骨骼肌中的表达量,pepck-m mRNA在肝脏中的表达量相对高于肾脏和骨骼肌中的表达量,均无显著差异(p>0.05)。孵化期胚胎肝脏中的PC mRNA含量显著高于成年鸡(p<0.05)。对肾脏而言,孵化第20d的pepck-C mRNA表达量显著高于孵化第14d pepck-C mRNA表达量(p<0.05)。Tukey-kramer法分析的结果显示,在孵化第14d、16d、18d和20d胚胎肝脏、肾脏和骨骼肌中pepck-m mRNA表达量均无明显变化。

关键词：鸡胚期 PC pepck-m pepck-C RT-PCR

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