Hydrogen ion dynamics and the Na+/H+ exchanger in cancer angiogenesis and antiangiogenesis

Orive, Gorka; Reshkin, Stephan J.; Harguindey, Salvador; Pedraz, José Luís

doi:10.1038/sj.bjc.6601286

Cited by 34 publications

(30 citation statements)

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“…Changes in pH, intracellular and extracellular calcium, osmolarity, and temperature appear to modulate NF-B activation by DNA-damaging agents. Interestingly, some of these changes can be observed with neoplastic transformation, within tumor microenvironments in various cancer types, and during radiation therapy and chemotherapy (8,33,43,64,71,92). Therefore, understanding the mechanisms responsible for enhancement (e.g., low pH, higher temperature) and the decrease (e.g., high osmolarity) of NF-B activation may provide novel strategies to prevent NF-B activation and to increase the efficacy of anticancer therapy.…”

Section: Discussionmentioning

confidence: 99%

Calcium-Dependent Regulation of NEMO Nuclear Export in Response to Genotoxic Stimuli

Berchtold

Huang

et al. 2007

Molecular and Cellular Biology

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The mechanisms involved in activation of the transcription factor NF-B by genotoxic agents are not well understood. Previously, we provided evidence that a regulatory subunit of the IB kinase (IKK) complex, NF-B essential modulator (NEMO)/IKK␥, is a component of a nuclear signal that is generated after DNA damage to mediate NF-B activation. Here, we found that etoposide (VP16) and camptothecin induced increases in intracellular free calcium levels at 60 min after stimulation of CEM T leukemic cells. Inhibition of calcium increases by calcium chelators, BAPTA-AM and EGTA-AM, abrogated NF-B activation by these agents in several cell types examined. Conversely, thapsigargin and ionomycin attenuated the BAPTA-AM effects and promoted NF-B activation by the genotoxic stimuli. Analyses of nuclear NEMO levels in VP16-treated cells suggested that calcium was required for nuclear export of NEMO. Inhibition of the nuclear exporter CRM1 by leptomycin B did not interfere with NEMO nuclear export. Similarly, deficiency of a plausible calcium-dependent nuclear export receptor, calreticulin, failed to prevent NF-B activation by VP16. However, temperature inactivation of the Ran guanine nucleotide exchange factor RCC1 in the tsBN2 cell line harboring a temperature-sensitive mutant of RCC1 blocked NF-B activation induced by genotoxic stimuli. Overexpression of Ran in this cell model showed that DNA damage stimuli induced formation of a complex between Ran and NEMO, suggesting that RCC1 regulated NF-B activation through the modulation of RanGTP. Indeed, evidence for VP16-inducible interaction between Ran-GTP and NEMO could be obtained by means of glutathione S-transferase (GST) pull-down assays using GST fused to the Ran binding domain of RanBP2, which specifically interacts with the GTP-bound form of Ran. BAPTA-AM did not alter these interactions, suggesting that calcium is a necessary step beyond the formation of a Ran-GTP-NEMO complex in the nucleus. These results suggest that calcium has a unique role in genotoxic stress-induced NF-B signaling by regulating nuclear export of NEMO subsequent to the formation of a nuclear export complex composed of Ran-GTP, NEMO, and presumably, an undefined nuclear export receptor.The Rel/NF-B family of transcription factors is regulated by a wide variety of extracellular stimuli, including growth factors, cytokines, and gentotoxic anticancer agents (2,12,34,46). The prototypical p50:p65(RelA) heterodimer is expressed in most mammalian cell types examined but kept inactive through the association of its inhibitor protein, such as IB␣. The inactive NF-B is primarily localized in the cytoplasm, and its activation involves its release from IB␣ and translocation to the nucleus. The release of NF-B from IB␣ can be accomplished by different mechanisms, including the well-characterized "canonical" pathway (17, 28, 55). In this pathway, different signaling events lead to the activation of the cytoplasmic IB kinase (IKK) complex, which mediates site-specific phosphorylation of IB␣. This phosphorylation ...

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Section: Discussionmentioning

confidence: 99%

Calcium-Dependent Regulation of NEMO Nuclear Export in Response to Genotoxic Stimuli

Berchtold

Huang

et al. 2007

Molecular and Cellular Biology

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“…We have learned from experimental and translational oncology that a key feature mediating the molecular mechanisms of action of the stimulation by the majority, if not all, of growth factors is an increase in the rate of exchange of Na + and H + ions and subsequent intracellular alkalinization, a phenomenon mediated mainly through the activation of the membrane-bound Na + /H + exchanger (NHE) [30,[42][43][44][45][46]. The NHE plays an essential pivotal role in the signal transduction of a multiplicity of intracellular signals induced by different hormones and trophic and growth factors by inducing an elevation of pH i [4,47,48].…”

Section: The Role Of the Na + /H + Exchanger In The Ph I -Mediated Apmentioning

confidence: 99%

Growth and Trophic Factors, pH and the Na+/H+ Exchanger in Alzheimers Disease, Other Neurodegenerative Diseases and Cancer: New Therapeutic Possibilities and Potential Dangers

Harguindey¹,

Reshkin²,

Orive³

et al. 2007

CAR

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Abnormalities in the intricate intracellular signalling pathways play a key role in the deregulation of either spontaneous (normal or pathological) or induced (therapeutic) cell death mechanisms. Some of these pathways are increasingly becoming molecular therapeutic targets in different processes, ranging from neurodegenerative diseases to cancer. Recent discoveries in research and treatment have shown that failure to induce selective cell apoptosis in hyperproliferative processes, like neoplastic diseases, and the failure to prevent spontaneous cell death in neurodegenerative diseases (HNDDs) such as Alzheimer's disease (AD), multiple sclerosis (MS), amyothrophic lateral sclerosis (ALS), Huntington's disease (HD), and retinitis pigmentosa (RP), can be interpreted as problems stemming from the same basic mechanisms but moving in diametrically opposed directions. The integrated approach advanced here represents an interdisciplinary attempt to stimulate an integrated vision of two otherwise widely separated areas of research, experimental neurology and oncology. This kind of approach to the prevention of apoptosis (therapeutic antiapoptosis) and/or other forms of cell death in HNNDs, as well as to resistance to therapeutic apoptosis in cancer (pathological antiapoptosis), has the scope to improve the understanding of the dualistic nature of the basic abnormalities underlying the pathological deregulation of cell death. In this context, an intracellular pH (pH(i))-related approach to these opposed situations is advanced to provide a unified theory of the apoptosis-antiapoptosis machinery. Some potential therapeutic possibilities opened by these lines of research, regarding the utilization of human growth factors and/or cellular anti-acidification measures directed to sustain cellular acid-base homeostasis in different HNNDs are considered because of their potential therapeutic benefit. Finally, we advance some possible dangers and side-effects raised by these very same treatment efforts.

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“…Additionally, tumors have localized areas characterized by spatial variations in pH e (5). The acidic pH of the tumor microenvironment is an important component driving tumor invasive capacity, neoangiogenesis, anchorage-independent growth, and genetic instability, which in combination contribute to malignant progression (5)(6)(7)(8). Moreover, low tumor pH e is a * This work was supported by Italian Association for Cancer Research Grant known factor responsible for the intrinsic resistance of malignant cells to chemotherapeutics (9,10) and negatively affects immune functions (11).…”

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confidence: 99%

Autophagy Is a Protective Mechanism for Human Melanoma Cells under Acidic Stress

Marino

Pellegrini

Lernia

et al. 2012

Journal of Biological Chemistry

160

133

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Background: Human melanoma cells are able to sustain low pH conditions characterizing many solid tumors. Results: Acidic stress in melanoma cells induces reduced nutrients uptake, inhibition of mammalian target of rapamycin, and activation of autophagy. Conclusion: Melanoma cells activate autophagy as a protective and adaptive response to acidic stress. Significance: Adaptation to acidosis via autophagy confirms the feasibility of anticancer therapy targeting autophagy.

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Hydrogen ion dynamics and the Na+/H+ exchanger in cancer angiogenesis and antiangiogenesis

Cited by 34 publications

References 34 publications

Calcium-Dependent Regulation of NEMO Nuclear Export in Response to Genotoxic Stimuli

Calcium-Dependent Regulation of NEMO Nuclear Export in Response to Genotoxic Stimuli

Growth and Trophic Factors, pH and the Na+/H+ Exchanger in Alzheimers Disease, Other Neurodegenerative Diseases and Cancer: New Therapeutic Possibilities and Potential Dangers

Autophagy Is a Protective Mechanism for Human Melanoma Cells under Acidic Stress

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