Ubiquitous Expression of the β - Subunit of H+-Transporting ATP Synthase on the Surface of Tumor Cells

Das, Ballabh; Mondragon-Escorpizo, Mary O.; Newman, Lisa A.; Sadeghian, Minoo; Tao, Shi-Zhen; Norin, Allen J.

doi:10.1007/978-1-4615-5955-9_32

Cited by 3 publications

(3 citation statements)

References 15 publications

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“…It remains to be seen whether plasma-membrane proton-pumps (Das et al, 1994;Chi and Pizzo, 2006) are used by the tumors for intracellular pH regulation as well.…”

Section: Monocarboxylate Transporters (Mcts): the "Pores" That Effluxmentioning

confidence: 99%

Lactate and malignant tumors: A therapeutic target at the end stage of glycolysis

Mathupala

Colen

Parajuli

et al. 2007

J Bioenerg Biomembr

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Metabolic aberrations in the form of altered flux through key metabolic pathways are primary hallmarks of many malignant tumors. Primarily the result of altered isozyme expression, these adaptations enhance the survival and proliferation of the tumor at the expense of surrounding normal tissue. Consequently, they also expose a unique set of targets for tumor destruction while sparing healthy tissues. Despite this fact, development of drugs to directly target such altered metabolic pathways of malignant tumors has been under-investigated until recently. One such target is the ultimate step of glycolysis, which, as expected, presents itself as a metabolic aberration in most malignant tumors. Termed "aerobic glycolysis" due to abnormal conversion of pyruvic acid to lactic acid even under normoxia, the altered metabolism requires these tumors to rapidly efflux lactic acid to the microenvironment in order to prevent poisoning themselves. Thus, exposed is a prime "choke-point" to target these highly malignant, frequently chemo-and radioresistant tumors. This review will focus on current outcomes in targeting lactate efflux in such tumors using glioma as a model, an ongoing project in our laboratory for the past half-decade, as well as supporting evidence from recent studies by others on targeting this "tail-end" of glycolysis in other tumor models.

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“…It remains to be seen whether plasma-membrane proton-pumps (Das et al, 1994;Chi and Pizzo, 2006) are used by the tumors for intracellular pH regulation as well.…”

Section: Monocarboxylate Transporters (Mcts): the "Pores" That Effluxmentioning

confidence: 99%

Lactate and malignant tumors: A therapeutic target at the end stage of glycolysis

Mathupala

Colen

Parajuli

et al. 2007

J Bioenerg Biomembr

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“…Extracellular ATP formation from ADP has been reported in cultures of several lines of human cells, including vascular endothelial cells, dermal keratinocytes, and some lines of tumor cells, and has been attributed to the activities of plasma membrane ATP synthase (PM-ATP synthase) 2 (1-7) and ecto forms of adenylate kinase (AK; ATP-AMP transphosphorylase, myokinase, EC 2.7.4.3) (5, 8 -12) and/or nucleoside diphosphokinase (8,(11)(12)(13)(14). F 1 F 0 -ATP synthase, the principal ATPforming apparatus of mitochondria and chloroplasts, is a complex, membrane-attached enzyme that generates ATP from ADP and P i , energized by a transmembrane proton gradient (15).…”

mentioning

confidence: 99%

Ectoadenylate Kinase and Plasma Membrane ATP Synthase Activities of Human Vascular Endothelial Cells

Quillen

Haslam

Samra

et al. 2006

Journal of Biological Chemistry

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Formation of ATP from ADP on the external surface of vascular endothelial cells has been attributed to plasma membrane ATP synthase, ectoadenylate kinase (ecto-AK), and/or ectonucleoside diphosphokinase. These enzymes or their catalytic products have been causatively linked to the elaboration of vascular networks and the regulation of capillary function. The amount of ATP generated extracellularly is small, requiring sensitive analytical methods for quantification. Human umbilical vein endothelial cells were used to revisit extracellular ATP synthesis using a reliable tetrazolium reduction assay and multiwell plate cultures. Test conditions compatible with AK stability were established. Extracellular AK activity was found to be <1% of the total (intracellular and extracellular), raising the possibility that the external enzyme could have leaked from living cells and/or a few dying cells. To determine whether AK inadvertently leaked from the cells, the activity of another cytoplasmic enzyme, glucose-6-phosphate dehydrogenase (G6PD), was also measured. G6PD is present in the cytoplasm in similar abundance to AK. The activity ratio of G6PD (extracellular/total) was found to be similar to that of AK. Because G6PD in the medium was probably due to leakage, other cytoplasmic macromolecules, including AK, should be released proportionately from the cells. The role of plasma membrane ATP synthase in extracellular ATP formation was examined using Hanks' balanced salt solution with and without selective inhibitors of AK and ATP synthase activities. With P 1 ,P 5 -di(adenosine 5)-pentaphosphate (inhibitor of AK activity), no extracellular ATP synthesis was detected, whereas with oligomycin, piceatannol, and aurovertin (inhibitors of F 1 F 0 -ATP synthase and F 1 -ATPase activities), no inhibition of extracellular ATP synthesis was observed. AK activity alone could account for the observed extracellular ATP synthesis. The possible impact of ADP impurity in the assays is discussed. Extracellular ATP formation from ADP has been reported in cultures of several lines of human cells, including vascular endothelial cells, dermal keratinocytes, and some lines of tumor cells, and has been attributed to the activities of plasma membrane ATP synthase (PM-ATP synthase) 2 (1-7) and ecto forms of adenylate kinase (AK; ATP-AMP transphosphorylase, myokinase, EC 2.7.4.3) (5, 8 -12) and/or nucleoside diphosphokinase (8,(11)(12)(13)(14). F 1 F 0 -ATP synthase, the principal ATPforming apparatus of mitochondria and chloroplasts, is a complex, membrane-attached enzyme that generates ATP from ADP and P i , energized by a transmembrane proton gradient (15). A cogent rationale for PM-ATP synthase in endothelial cells has yet to be developed, even though there are reports that, within the plasma membrane, the protein complex itself may play a regulatory role in angiogenesis, i.e. the process of elaborating the blood capillary network in undervascularized tissues (1, 3, 4). AK, which is widely distributed within the plant and animal kingdoms, is l...

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“…subunit, which extends into the mitochondrial matrix and catalyzes the formation of ATP from ADP and inorganic phosphate (for review see [106]). While it was originally thought that ATP synthase was localized and active only in the mitochondria, recent evidence has detected the enzyme at the plasma membrane of a number of cell types, including vascular endothelial cells [107][108][109][110]. Angiostatin, a product of plasminogen cleavage in the fibrinolytic system, exhibits high affinity binding to the alpha and beta subunits of the F 1 subunit of ATP synthase in membrane fractions from HUVECs and has been identified as a potent inhibitor of angiogenesis and tumor development [107,111,112].…”

Section: Abc Transportersmentioning

confidence: 99%

Function and Regulation of Pannexin 1 Channels in the Vascular Endothelium

Lohman¹

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The nucleotide adenosine 5'-triphosphate (ATP) has classically been considered the cell's primary energy currency; however, a novel role for ATP as an extracellular autocrine/paracrine signaling molecule has evolved over the past century. Purinergic signaling is now known to regulate a plethora of physiological and pathophysiological processes in almost every organ system. In the vasculature, ATP and its metabolites elicit dual control over blood vessel tone and tissue perfusion, and purinergic signaling events have been implicated in vascular pathologies including atherosclerosis and inflammation.While the importance of extracellular ATP in the vascular system is well recognized, the mechanism(s) mediating the regulated release of the purine from vascular cells are less well understood and are a key target of current investigation. One such ATP-liberation mechanism has been ascribed to the recently identified pannexin (Panx) channels, namely Panx1. Initially, we characterized the expression and localization profiles of Panx isoforms across the systemic vasculature, identifying predominant representation by the Panx1 isoform in both smooth muscle (SMC) and endothelial cells (EC) comprising the blood vessel wall, with more heterogeneous expression profiles observed in specialized vascular systems including the heart, lung and kidney. In particular, the Panx1 isoform is highly expressed in ECs regardless of blood vessel type or size, while Panx1 expression is limited to SMCs of small arteries and arterioles. Panx1 forms hexameric channels in the plasma membrane of ECs, functioning to release ATP in response to a number of stimuli. However, prolonged Panx1 channel activity is extremely detrimental to cell viability. Here we report a novel negative regulatory mechanism that may govern the activity of Panx1 channels in ECs, by which the bioactive gas nitric oxide (NO) covalently modifies two cysteine (Cys) residues in the channel by a process termed S- reinforce the dual effect of purines on peripheral resistance and blood pressure. Purinergic Control of Vascular InflammationWhile the foundation for purinergic control of vascular functions was initially characterized extensively in the context of vascular reactivity and overall blood flow and pressure regulation, it has become increasingly clear that extracellular ATP also plays important regulatory roles in the vascular inflammatory response. Vascular inflammation can be characterized as acute (physiological) or chronic (pathological) in nature.The acute vascular inflammatory response is an innate process of inflammatory cell homing to infected or damaged tissues resulting from integrated cross-talk between circulating leukocytes and the vascular endothelium, primarily at the level of postcapillary venules [61]. This process has been highly studied and is now known to occur in a step-wise manner beginning with local recruitment, rolling (fast and slow), adhesion and final extravasation into the surrounding tissue (reviewed in [62...

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Ubiquitous Expression of the β - Subunit of H+-Transporting ATP Synthase on the Surface of Tumor Cells

Cited by 3 publications

References 15 publications

Lactate and malignant tumors: A therapeutic target at the end stage of glycolysis

Lactate and malignant tumors: A therapeutic target at the end stage of glycolysis

Ectoadenylate Kinase and Plasma Membrane ATP Synthase Activities of Human Vascular Endothelial Cells

Function and Regulation of Pannexin 1 Channels in the Vascular Endothelium

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