Increased pH and tumorigenicity of fibroblasts expressing a yeast proton pump

Perona, Rosario; Serrano, Ramón

doi:10.1038/334438a0

Cited by 188 publications

(118 citation statements)

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“…These data indicate that the distribution of V-ATPase at the cell surface is responsible for the increased J H ϩ observed in highly metastatic cells and that V-ATPase is positioned at the cell surface to extrude H ϩ across the plasma membrane. Early studies from the yeast H ϩ -ATPase-transfected cell model have suggested that overexpression of proton pumps on the cell membrane can increase the pH cyt , trigger cell proliferation, and finally causes tumorigenesis (12,36). The present study indicates that V-ATPase overexpression at the cell surface increases the J H ϩ and is responsible for a more metastatic phenotype.…”

Section: Discussionmentioning

confidence: 53%

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Vacuolar H⁺-ATPase in human breast cancer cells with distinct metastatic potential: distribution and functional activity

Sennoune

Bakunts

Martı́nez

et al. 2004

American Journal of Physiology-Cell Physiology

312

309

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cells thrive in a hypoxic microenvironment with an acidic extracellular pH. To survive in this harsh environment, tumor cells must exhibit a dynamic cytosolic pH regulatory system. We hypothesize that vacuolar H ϩ -ATPases (V-ATPases) that normally reside in acidic organelles are also located at the cell surface, thus regulating cytosolic pH and exacerbating the migratory ability of metastatic cells. Immunocytochemical data revealed for the first time that VATPase is located at the plasma membrane of human breast cancer cells: prominent in the highly metastatic and inconspicuous in the lowly metastatic cells. The V-ATPase activities in isolated plasma membranes were greater in highly than in lowly metastatic cells. The proton fluxes via V-ATPase evaluated by fluorescence spectroscopy in living cells were greater in highly than in lowly metastatic cells. Interestingly, lowly metastatic cells preferentially used the ubiquitous Na ϩ /H ϩ exchanger and HCO 3 Ϫ -based H ϩ -transporting mechanisms, whereas highly metastatic cells used plasma membrane V-ATPases. The highly metastatic cells were more invasive and migratory than the lowly metastatic cells. V-ATPase inhibitors decreased the invasion and migration in the highly metastatic cells. Altogether, these data indicate that V-ATPases located at the plasma membrane are involved in the acquisition of a more metastatic phenotype. metastasis; intracellular pH; migration; sodium ion/hydrogen ion exchanger; bicarbonate transport MAINTENANCE OF CYTOSOLIC pH (pH cyt ) is crucial to normal cell function because many cellular processes have a narrow pH optimum (38). Tumor cells possess high-glycolytic activity and produce acidic metabolites (39). Moreover, tumor cells often exist in a hypoxic microenvironment with a lower extracellular pH (pH ex ) than that of surrounding normal cells (10,15,40). Acidic pH ex and hypoxic environment are not permissive for cell growth and have been associated with apoptosis (14, 25). To minimize the potentially toxic reduction in pH cyt that would accompany growth in a chronically acidic environment, tumor cells must upregulate the proton extrusion mechanism(s) that maintains pH cyt . The ability to upregulate proton extrusion may be essential for tumor cell survival. The influence of pH cyt on many cellular functions has been studied with respect to cell growth (16), cell motility (27), tumorigenesis (36), metastasis (45), apoptosis (14), and drug resistance in cancer cells (28, 50).Four major types of pH cyt regulatory mechanisms have been identified in tumor cells: Na ϩ /H ϩ exchangers, bicarbonate (HCO 3 Ϫ ) transporters, proton-lactate symporters, and proton pumps (11,38,42). Recently, the vacuolar H ϩ -ATPase (VATPase) has emerged as a novel and important pH cyt regulatory system in some specialized cells, including tumor (25,26,28). This proton pump is ubiquitously expressed (33, 35), not only in vacuolar membranes but also in plasma membranes (26, 58) of eukaryotic cells. The V-ATPase is a multi-subunit enzyme complex composed of a me...

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Section: Discussionmentioning

confidence: 53%

“…The ability to upregulate proton extrusion may be essential for tumor cell survival. The influence of pH cyt on many cellular functions has been studied with respect to cell growth (16), cell motility (27), tumorigenesis (36), metastasis (45), apoptosis (14), and drug resistance in cancer cells (28,50).…”

mentioning

confidence: 99%

Vacuolar H⁺-ATPase in human breast cancer cells with distinct metastatic potential: distribution and functional activity

Sennoune

Bakunts

Martı́nez

et al. 2004

American Journal of Physiology-Cell Physiology

312

309

View full text Add to dashboard Cite

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“…Significant correlations have been found between neoplastic potential and bioelectrical properties of cells (45)(46)(47)(48)(49). These biophysical properties are not simply markers but are functional signals; misexpression of an ion transporter induces tumorigenicity in fibroblasts (50), and inhibition of EAG channel function suppresses neoplasm in an animal model in vivo (51). Ion channel function controls the proliferation rate and invasiveness of a number of cell types that often form tumors (49,(52)(53)(54)(55), and overexpression of KCNK9 (strongly overexpressed in breast cancer) promotes tumor formation and confers resistance to hypoxia and serum deprivation (56).…”

Section: Discussionmentioning

confidence: 97%

Modulation of potassium channel function confers a hyperproliferative invasive phenotype on embryonic stem cells

Morokuma¹,

Blackiston²,

Adams³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

102

124

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Ion transporters, and the resulting voltage gradients and electric fields, have been implicated in embryonic development and regeneration. These biophysical signals are key physiological aspects of the microenvironment that epigenetically regulate stem and tumor cell behavior. Here, we identify a previously unrecognized function for KCNQ1, a potassium channel known to be involved in human Romano-Ward and Jervell-Lange-Nielsen syndromes when mutated. Misexpression of its modulatory wild-type ␤-subunit XKCNE1 in the Xenopus embryo resulted in a striking alteration of the behavior of one type of embryonic stem cell: the pigment cell lineage of the neural crest. Depolarization of embryonic cells by misexpression of KCNE1 non-cell-autonomously induced melanocytes to overproliferate, spread out, and become highly invasive of blood vessels, liver, gut, and neural tube, leading to a deeply hyperpigmented phenotype. This effect is mediated by the up-regulation of Sox10 and Slug genes, thus linking alterations in ion channel function to the control of migration, shape, and mitosis rates during embryonic morphogenesis. Taken together, these data identify a role for the KCNQ1 channel in regulating key cell behaviors and reveal the molecular identity of a biophysical switch, by means of which neoplastic-like properties can be conferred upon a specific embryonic stem cell subpopulation.cancer ͉ ion channel ͉ melanocyte ͉ neural crest ͉ KCNQ

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“…Modifying pHi by implanting and activating a yeast Na+/ H+ ATPase gene in murine fibroblasts causes tumours in nude mice, whereas the control murine fibroblasts failed to establish (Perona & Serrano, 1988), suggesting that the alkaline pHi triggered uncontrolled mitosis.…”

Section: Discussionmentioning

confidence: 99%

Human primary brain tumour metabolism in vivo: a phosphorus magnetic resonance spectroscopy study

Cadoux-Hudson

Blackledge²,

Rajagopalan³

et al. 1989

Br J Cancer

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Summary Magnetic resonance spectroscopy was used to study intracellular pH and compounds which contain phosphorus in normal human brain and primary brain tumours non-invasively. In normal subjects (n=7) intracellular pH (pHi) of the brain was 7.03+0.02 (mean±s.e.m.). The pHi did not vary between superficial (2cm, majority grey matter) and deep brain (5cm, majority white matter). The relative concentrations of phosphocreatine (PCr) and phosphomonoesters (PME) to ATP were also constant with depth. The relative concentration of phosphodiesters (PDE) increased from superficial to deep in normal brain. The astrocytomas (n = 7, grade II-IV) were significantly more alkaline (pHi = 7.08 + 0.03), and contained more PCr and PME, with respect to ATP, than normal brain at similar depth. The meningiomas (n = 4) were also more alkaline (pHi = 7.19 + 0.02) with a raised PME level but reduced PCr. The reduction in meningioma PCr may be due to the significant necrosis (>20 %) seen in the surgical biopsies. No significant necrosis was seen in the gliomas. Previous in vitro studies suggest that increased PME may be due to accumulation of phosphoethanolamine (PE), a phospholipid precursor. These results suggest that human primary brain tumours characteristically are more alkaline with increased PME than normal brain.Magnetic resonance spectroscopy (MRS) offers a noninvasive, non-disruptive method of studying intra-cellular metabolism in vivo. The development of wide bore magnets has allowed 31P MRS to be applied to the study of tumours in humans. Differences between the biochemistry of normal and neoplastic tissues have been used to design optimum forms of chemotherapy. This technique gives information on phosphocreatine (PCr), ATP, inorganic phosphate (Pi) levels and phosphomonester (PME) and phosphodiester (PDE) containing compounds within the cell, and on intracellular pH (pHi) (Radda, 1986).PCr, ATP and Pi are compounds involved in energy transfer within the cell. The intracellular levels of these compounds are determined in part by the balance between substrate supply and energy demand. PME and PDE peaks contain signal derived from compounds which are involved in phospholipid synthesis and degradation . Relative levels of PME and PDE may reflect differing rates of cell turnover. Animal and tissue culture tumour models have been studied using phosphorus MRS (Daly et al., 1987;Miceli et al., 1988). These studies have shown a consistently raised PME peak within the neoplastic cell. The PME peak was mainly composed of phosphoethanolamine (PE), a precursor in phospholipid synthesis. Human studies of neuroblastoma and other tumours in vivo have also found a raised PME peak (Maris et al., 1985) and alkaline pHi relative to normal tissue in some brain tumours (Oberhaensli et al., 1986).The aim of this study was to investigate the phosphorus metabolism of normal brain and primary brain tumours and relate biochemical differences to histological features seen in the tumour biopsies taken within 24h of the MRS study. The phase modulated r...

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Increased pH and tumorigenicity of fibroblasts expressing a yeast proton pump

Cited by 188 publications

References 15 publications

Vacuolar H⁺-ATPase in human breast cancer cells with distinct metastatic potential: distribution and functional activity

Vacuolar H⁺-ATPase in human breast cancer cells with distinct metastatic potential: distribution and functional activity

Modulation of potassium channel function confers a hyperproliferative invasive phenotype on embryonic stem cells

Human primary brain tumour metabolism in vivo: a phosphorus magnetic resonance spectroscopy study

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Increased pH and tumorigenicity of fibroblasts expressing a yeast proton pump

Cited by 188 publications

References 15 publications

Vacuolar H+-ATPase in human breast cancer cells with distinct metastatic potential: distribution and functional activity

Vacuolar H+-ATPase in human breast cancer cells with distinct metastatic potential: distribution and functional activity

Modulation of potassium channel function confers a hyperproliferative invasive phenotype on embryonic stem cells

Human primary brain tumour metabolism in vivo: a phosphorus magnetic resonance spectroscopy study

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Product

Resources

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Vacuolar H⁺-ATPase in human breast cancer cells with distinct metastatic potential: distribution and functional activity

Vacuolar H⁺-ATPase in human breast cancer cells with distinct metastatic potential: distribution and functional activity