Na+/H+ exchanger‐dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation‐associated phenotypes

  title={Na+/H+ exchanger‐dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation‐associated phenotypes},
  author={Stephan Joel Reshkin and Antonia Bellizzi and Sandra Caldeira and Valentina Albarani and Ilaria Malanchi and Manuela Poignee and Marianna Alunni-Fabbroni and Valeria Casavola and Massimo Tommasino},
  journal={The FASEB Journal},
  pages={2185 - 2197}
In this study we investigate the mechanism of intracellular pH change and its role in malignant transformation using the E7 oncogene of human papillomavirus type 16 (HPV16). Infecting NIH3T3 cells with recombinant retroviruses expressing the HPV16 E7 or a transformation deficient mutant we show that alkalinization is transformation specific. In NIH3T3 cells in which transformation can be turned on and followed by induction of the HPV16 E7 oncogene expression, we demonstrate that cytoplasmic… 

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Regulation of the Na+/H+ Exchanger (NHE1) in Breast Cancer Metastasis.

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Na+/H+ Exchangers and RhoA Regulate Acidic Extracellular pH‐Induced Lysosome Trafficking in Prostate Cancer Cells

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Na(+)/H(+)flux, as mediated by the sodium-hydrogen exchanger isoform 1 (NHE1), a major ion transporter involved in tumourigenesis, is discussed and the potential for targeting NHE1 in the development of novel chemotherapeutic applications is explored.

The role of translation elongation factor eEF1A in intracellular alkalinization-induced tumor cell growth

The above findings suggest that an increase in free-form eEF1A under alkaline conditions plays a critical role in alkalinization-induced cell growth.

Hypoxia-Induced Invadopodia Formation Involves Activation of NHE-1 by the p90 Ribosomal S6 Kinase (p90RSK)

It is shown that hypoxia stimulates the formation of invadopodia as well as the invasive ability of cancer cells, and establishes p90RS kinase as a link between Hypoxia and the acidic microenvironment of tumors.

The Na+/H+ exchanger NHE1 in stress-induced signal transduction: implications for cell proliferation and cell death

New findings implicating NHE1 activation as a central signaling event activated by stress conditions and modulating cell proliferation and death are presented and discussed.



Requirement of the Na+/H+ exchanger for tumor growth.

The results suggest that the Na+/H+ exchanger is important for tumor growth, and cells derived from the few tumors which grew after implantation of HSPD mutant cells were revertants which had regained Na+.

Increased pH and tumorigenicity of fibroblasts expressing a yeast proton pump

A crucial role of intracellular pH in the growth control of animal cells is supported and a more specific approach which involves expressing the gene for the yeast plasma membrane H+-ATPase7 in fibroblasts is introduced, suggesting that the yeast ATPase gene behaves as an oncogene in mammalian cells.

Tumorigenic 3T3 cells maintain an alkaline intracellular pH under physiological conditions.

It is shown that transfected NIH 3T3 cells with yeast H(+)-ATPase do maintain a higher pHin than control cells in the presence of HCO3- and that these cells are serum-independent for growth and that they glycolyze much more rapidly than phenotypically normal cells.

Activity and density of the Na+/H+ antiporter in normal and transformed human lymphocytes and fibroblasts.

The turnover number of NHE-1 is significantly increased after viral transformation, which correlates with the increased proliferation rate of these transformed cells, but the intracellular pH and Na+/H+ antiport activity of these cells was elevated.

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Ability of the HPV16 E7 protein to bind RB and induce DNA synthesis is not sufficient for efficient transforming activity in NIH3T3 cells.

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Role of Intracellular pH in Proliferation, Transformation, and Apoptosis

It is concluded that the cytosolic pH, an essential physiological parameter that is tightly controlled by multiple, complementary, or redundant systems, is unlikely to play a role in signalling either cell growth or death.

Apoptosis in an Interleukin-2-dependent Cytotoxic T Lymphocyte Cell Line Is Associated with Intracellular Acidification

It is demonstrated that apoptotic cells retain a functional antiport but that its set-point has changed, suggesting that an acid pH is not essential for apoptosis, and that other critical regulators of apoptosis must be subject to dephosphorylation.

Molecular physiology of vertebrate Na+/H+ exchangers.

This review describes recent progress concerning the molecular aspects of the Na+/H+ exchanger, an important regulator for intracellular pH, cell volume, and transepithelial Na+ transport that is regulated in response to a variety of extracellular stimuli.