The Na+/H+ exchanger NHE1, but not the Na+, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" altimg="si1.gif" overflow="scroll"><mml:mrow><mml:msubsup><mml:mrow><mml:mtext>HCO</mml:mtext></mml:mrow><mml:mrow><mml:mn>3</mml:mn></mml:mrow><mml:mrow><mml:mo>-</mml:mo></mml:mrow></mml:msubsup></mml:mrow></mml:math> cotransporter NBCn1, regulates motility of MCF7 breast cancer cells expressing constitutively active ErbB2

Lauritzen, Gitte; Stock, C C; Lemaire, J.-J.; Lund, Stine F.; Jensen, Mie Birgitte Frid; Damsgaard, Britt; Petersen, Katrine Seide; Wiwel, Maria; Rønnov‐Jessen, Lone; Schwab, Albrecht; Pedersen, Stine Falsig

doi:10.1016/j.canlet.2011.11.023

Cited by 103 publications

(85 citation statements)

References 63 publications

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“…Subsequent work showed that the pH i -dependent proliferative response in cancer cells can be generated by distinct ion transport proteins, including NHE1 (Lauritzen et al, 2012), Na + -driven bicarbonate transporters (Boedtkjer et al, 2013;McIntyre et al, 2016) and the H + /K + -ATPase proton pump (Goh et al, 2014). Additionally, pH i -dependent proliferation has recently been confirmed in vivo (Grillo-Hill et al, 2015).…”

Section: Proliferation and Cell Survivalmentioning

confidence: 99%

“…Evidence suggests that NHE1 is a significant contributor to matrix degradation through local extracellular acidification or effects on MMP expression and localization (Lin et al, 2012;Putney and Barber, 2004). Increased pH i resulting from ion transporter activity has been shown to enable cancer cell migration in oncogene-transformed mammary cells (Lauritzen et al, 2012), in patient-derived glioma cell lines (Cong et al, 2014) and in cervical cancer cell lines that do not exhibit hallmarks of metabolic adaptation (De Saedeleer et al, 2014). Furthermore, increased pH i due to higher ion transporter activity has been linked to cell invasion phenotypes (Lin et al, 2012;Grillo-Hill et al, 2015).…”

Section: Migration and Metastasismentioning

confidence: 99%

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Cancer cell behaviors mediated by dysregulated pH dynamics at a glance

White

Grillo-Hill

Barber

2017

Journal of Cell Science

296

312

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Dysregulated pH is a common characteristic of cancer cells, as they have an increased intracellular pH ( pH i ) and a decreased extracellular pH ( pH e ) compared with normal cells. Recent work has expanded our knowledge of how dysregulated pH dynamics influences cancer cell behaviors, including proliferation, metastasis, metabolic adaptation and tumorigenesis. Emerging data suggest that the dysregulated pH of cancers enables these specific cell behaviors by altering the structure and function of selective pH-sensitive proteins, termed pH sensors. Recent findings also show that, by blocking pH i increases, cancer cell behaviors can be attenuated. This suggests ion transporter inhibition as an effective therapeutic approach, either singly or in combination with targeted therapies. In this Cell Science at a Glance article and accompanying poster, we highlight the interconnected roles of dysregulated pH dynamics in cancer initiation, progression and adaptation.

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Section: Proliferation and Cell Survivalmentioning

confidence: 99%

Section: Migration and Metastasismentioning

confidence: 99%

Cancer cell behaviors mediated by dysregulated pH dynamics at a glance

White

Grillo-Hill

Barber

2017

Journal of Cell Science

296

312

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“…We also investigated the sodium/ hydrogen exchanger 1 (NHE1). NHE1 is involved in cellular events important for normal intestinal function such as cell migration [247] and volume regulation [248].…”

Section: Aqp6 Overexpression Reduces the Infectivity Of Hazara Virusmentioning

confidence: 99%

Aquaporins in Infection and Inflammation

Holm¹

2016

Linköping University Medical Dissertations

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About the cover:The front cover displays a human, blood-derived macrophage stained for aquaporin 9.During the course of the research underlying this thesis, Angelika Holm was enrolled in Forum Scientium, a multidisciplinary doctoral programme at Linköping University Printed by LiU-Tryck, Linköping, Sweden, 2016 "Be brave, even if you're not, pretend to be. No one can tell the difference."To that young, awkward, tall girl who dared to dream of something else, something more:You did it. SUPERVISOR Elena VikströmDepartment of Clinical and Experimental Medicine Linköping University Linköping Sweden When cells of the innate immune system encounter pathogens they need to respond and prepare for migration and phagocytosis and do so through volume regulatory processes. The Gramnegative bacterium Pseudomonas aeruginosa utilizes a small molecule-based communication system, called quorum sensing (QS) to control the production of its virulence factors and biofilms. We found that P. aeruginosa with a complete QS system elicits a stronger phagocytic response in human blood-derived macrophages compared to its lasI-/rhlI-mutant lacking the production of the QS molecules N-butyryl-L-homoserine lactone (C4-HSL) and N-3-oxododecanoyl-L-homoserine lactone (3O-C12-HSL). Infection with P. aeruginosa further increases the expression of AQP9 and induces re-localisation of AQP9 to the front and trailing ends of macrophages. Moreover, the 3O-C12-HSL alone elevates the expression of AQP9, redistribute the water channel to the front and rear ends and increases the cell area and volume of macrophages. Both infection with the wild type P. aeruginosa and the treatment with 3O-C12-HSL change the nano-structural architecture of the AQP9 distribution in macrophages. ASSISTANT SUPERVISORS Karl-Eric MagnussonViruses use the intracellular machinery of the invaded cells to produce and assemble new viral bodies. Intracellular AQPs are localised in a membranes of cellular organelles to regulate their function and morphology. C3H10T1/2 fibroblasts transiently expressing green fluorescent protein (GFP)-AQP6 show a reduced expression of AQP6 after Hazara virus infection and an increased cell area. Overexpressing AQP6 in C3H10T1/2 cells reduces the infectivity of Hazara virus indicating that AQP6 expression has a protective role in virus infections.Ion and water channels in the epithelial cell lining tightly regulate the water homeostasis. In microscopic colitis (MC), patients suffer from severe watery diarrhoeas. For the first time, we have shown that the expression of AQP1, 8 and 11 and the sodium/hydrogen exchanger NHE1 are reduced in colonic biopsies from MC patients compared to healthy control individuals. Following treatment with the glucocorticoid budesonide the patients experienced a rapid recovery and we observed a restored or increased expression of the AQPs and NHE1 during treatment, suggesting a role for AQPs in the diarrhoeal mechanisms in MC.Taken together, this thesis provides new evidence on the importance of water homeostasis regulatio...

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“…NHE1 localizes to the leading edge membrane of migrating cells as well as to adhesive/invasive structures such as invadopodial rosettes (Lagana et al, 2000;Lauritzen et al, 2012;Martin et al, 2011;Patel and Barber, 2005), anchors the actin cytoskeleton to the plasma membrane (Denker et al, 2000;Wu et al, 2004) and interacts with integrins (Yi et al, 2009). NHE1 expression is upregulated during quiescence concomitant with formation of the primary cilium (Schneider et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

PDGFRα signaling in the primary cilium regulates NHE1-dependent fibroblast migration via coordinated differential activity of MEK1/2-ERK1/2-p90RSK and AKT signaling pathways

Clement

Mally

Stock

et al. 2012

Journal of Cell Science

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SummaryIn fibroblasts, platelet-derived growth factor receptor alpha (PDGFRa) is upregulated during growth arrest and compartmentalized to the primary cilium. PDGF-AA mediated activation of the dimerized ciliary receptor produces a phosphorylation cascade through the PI3K-AKT and MEK1/2-ERK1/2 pathways leading to the activation of the Na + /H + exchanger, NHE1, cytoplasmic alkalinization and actin nucleation at the lamellipodium that supports directional cell migration. We here show that AKT and MEK1/2-ERK1/2-p90 RSK inhibition reduced PDGF-AA-induced cell migration by distinct mechanisms: AKT inhibition reduced NHE1 activity by blocking the translocation of NHE1 to the cell membrane. MEK1/2 inhibition did not affect NHE1 activity but influenced NHE1 localization, causing NHE1 to localize discontinuously in patches along the plasma membrane, rather than preferentially at the lamellipodium. We also provide direct evidence of NHE1 translocation through the cytoplasm to the leading edge. In conclusion, signals initiated at the primary cilium through the PDGFRaa cascade reorganize the cytoskeleton to regulate cell migration differentially through the AKT and the MEK1/2-ERK1/2-p90 RSK pathways. The AKT pathway is necessary for initiation of NHE1 translocation, presumably in vesicles, to the leading edge and for its activation. In contrast, the MEK1/2-ERK1/2-p90 RSK pathway controls the spatial organization of NHE1 translocation and incorporation, and therefore specifies the direction of the leading edge formation.

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The Na+/H+ exchanger NHE1, but not the Na+, HCO3- cotransporter NBCn1, regulates motility of MCF7 breast cancer cells expressing constitutively active ErbB2

Cited by 103 publications

References 63 publications

Cancer cell behaviors mediated by dysregulated pH dynamics at a glance

Cancer cell behaviors mediated by dysregulated pH dynamics at a glance

Aquaporins in Infection and Inflammation

PDGFRα signaling in the primary cilium regulates NHE1-dependent fibroblast migration via coordinated differential activity of MEK1/2-ERK1/2-p90RSK and AKT signaling pathways

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