Plasmalemmal V-H+-ATPases regulate intracellular pH in human lung microvascular endothelial cells

Rojas, José D.; Sennoune, Souad R.; Maiti, Debasish; Martı́nez, Gloria; Bakunts, Karina; Wesson, Donald E.; Martı́nez-Zaguilán, Raul

doi:10.1016/j.bbrc.2004.06.068

Cited by 12 publications

(8 citation statements)

References 47 publications

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“…Mammalian non-neuronal cells transfected with ChAT gain the property to release ACh only when they are co-transfected with this proteolipid and when it is targeted to the plasma membrane (Bloc et al 1999 ; Morel 2003 ). Interestingly, the V–ATPase complex is localized to the plasma membrane in human lung microvascular endothelial cells (Rojas et al 2004 ) and rabbit alveolar macrophages (Heming and Bidani 2003 ), so that “mediatophore” may mediate ACh release from these cells.…”

Section: Ach Synthesis and Recycling In Non-neuronal Cellsmentioning

confidence: 99%

The epithelial cholinergic system of the airways

Kummer

Lips

Pfeil

2008

Histochem Cell Biol

178

146

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Acetylcholine (ACh), a classical transmitter of parasympathetic nerve Wbres in the airways, is also synthesized by a large number of non-neuronal cells, including airway surface epithelial cells. Strongest expression of cholinergic traits is observed in neuroendocrine and brush cells but other epithelial cell types-ciliated, basal and secretory-are cholinergic as well. There is cell type-speciWc expression of the molecular pathways of ACh release, including both the vesicular storage and exocytotic release known from neurons, and transmembrane release from the cytosol via organic cation transporters. The subcellular distribution of the ACh release machineries suggests luminal release from ciliated and secretory cells, and basolateral release from neuroendocrine cells. The scenario as known so far strongly suggests a local auto-/paracrine role of epithelial ACh in regulating various aspects on the innate mucosal defence mechanisms, including mucociliary clearance, regulation of macrophage function and modulation of sensory nerve Wbre activity. The proliferative eVects of ACh gain importance in recently identiWed ACh receptor disorders conferring susceptibility to lung cancer. The cell type-speciWc molecular diversity of the epithelial ACh synthesis and release machinery implies that it is diVerently regulated than neuronal ACh release and can be speciWcally targeted by appropriate drugs.

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Section: Ach Synthesis and Recycling In Non-neuronal Cellsmentioning

confidence: 99%

The epithelial cholinergic system of the airways

Kummer

Lips

Pfeil

2008

Histochem Cell Biol

178

146

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“…Targeting the proton pump v-ATPase for cancer therapy has gained great interest since its inhibition was reported to reduce the invasiveness of cancer cells and, most importantly, also metastasis [ 8 , 9 ]. Thus, intensive research related to v-ATPases was done in cancer cells, whereas there are only few studies investigating v-ATPases in endothelial cells indicating a role in migration, proliferation and possibly angiogenesis [ 22 – 24 ]. In the present study we used the myxobacterial natural product archazolid to investigate the consequences of v-ATPase inhibition in the endothelium on tumor-endothelial cell interactions.…”

Section: Discussionmentioning

confidence: 99%

“…This adhesive interaction is mediated by receptors and corresponding ligands expressed on tumor and endothelial cells [ 18 , 21 ]. V-ATPases have been reported to regulate intracellular pH and cell migration in microvascular endothelial cells [ 22 , 23 ]. A recent study showed that the inhibition of v-ATPase by concanamycin prevented proliferation, reduced migration and impaired angiogenesis-related signaling in endothelial cells [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

The vacuolar-type ATPase inhibitor archazolid increases tumor cell adhesion to endothelial cells by accumulating extracellular collagen

et al. 2018

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The vacuolar-type H+-ATPase (v-ATPase) is the major proton pump that acidifies intracellular compartments of eukaryotic cells. Since the inhibition of v-ATPase resulted in anti-tumor and anti-metastatic effects in different tumor models, this enzyme has emerged as promising strategy against cancer. Here, we used the well-established v-ATPase inhibitor archazolid, a natural product first isolated from the myxobacterium Archangium gephyra, to study the consequences of v-ATPase inhibition in endothelial cells (ECs), in particular on the interaction between ECs and cancer cells, which has been neglected so far. Human endothelial cells treated with archazolid showed an increased adhesion of tumor cells, whereas the transendothelial migration of tumor cells was reduced. The adhesion process was independent from the EC adhesion molecules ICAM-1, VCAM-1, E-selectin and N-cadherin. Instead, the adhesion was mediated by β1-integrins expressed on tumor cells, as blocking of the integrin β1 subunit reversed this process. Tumor cells preferentially adhered to the β1-integrin ligand collagen and archazolid led to an increase in the amount of collagen on the surface of ECs. The accumulation of collagen was accompanied by a strong decrease of the expression and activity of the protease cathepsin B. Overexpression of cathepsin B in ECs prevented the capability of archazolid to increase the adhesion of tumor cells onto ECs. Our study demonstrates that the inhibition of v-ATPase by archazolid induces a pro-adhesive phenotype in endothelial cells that promotes their interaction with cancer cells, whereas the transmigration of tumor cells was reduced. These findings further support archazolid as a promising anti-metastatic compound.

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“…Consequently, the mechanisms for acid release were HCO 3 --independent. A possible candidate for the DMAinsensitive mechanism is the vacuolar H + -ATPase, recently shown to contribute to the regulation of cytosolic pH in human epithelial and endothelial cells [Inglis et al, 2003;Lang et al, 2003;Rojas et al, 2004] and to be expressed in A549 cells [Ran et al 2003]. It was also demonstrated in paper I that perfusion of cells at high-density with dust (and LPS) caused a blockade of acid release, which most likely would lead to intracellular acidosis in these cells.…”

Section: A) B) C)mentioning

confidence: 94%

Untitled

Burvall

Palmberg

Larsson

2002

Molecular and Cellular Biochemistry

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Genistein is often used as an inhibitor of tyrosine kinases. A less studied side effect of genistein is an inhibition of cyclic AMP-phosphodiesterase (cAMP-PDE) activity resulting in increased cAMP accumulation. The effect of genistein on intracellular cAMP-levels, basal and forskolin-induced, was studied in A549 human airway epithelial cells and compared with the unspecific PDE inhibitor, isobutylmethylxanthine (IBMX). It was shown that genistein (50 microM) increased basal cAMP and potentiated forskolin-induced cAMP accumulation to the same extent as IBMX (100 microM). Thus, the use of genistein in studies on signaling transductions may result in erroneous conclusions since increased cAMP may cause or contribute to the observed effects.

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Plasmalemmal V-H+-ATPases regulate intracellular pH in human lung microvascular endothelial cells

Cited by 12 publications

References 47 publications

The epithelial cholinergic system of the airways

The epithelial cholinergic system of the airways

The vacuolar-type ATPase inhibitor archazolid increases tumor cell adhesion to endothelial cells by accumulating extracellular collagen

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