The human Na+/H+ exchanger 1 is a membrane scaffold protein for extracellular signal-regulated kinase 2

Hendus-Altenburger, Ruth; Pedraz-Cuesta, Elena; Olesen, Christina W.; Papaleo, Elena; Schnell, Jeff A.; Hopper, Jonathan T. S.; Robinson, Carol V.; Pedersen, Stine Falsig; Kragelund, Birthe B.

doi:10.1186/s12915-016-0252-7

Cited by 51 publications

(44 citation statements)

References 83 publications

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“…33,34 While an increase in pH i is sufficient to induce dysplasia at least under some conditions, 35 it is also well accepted that at least NHE1 plays additional roles, including scaffolding of signaling components. 36,37 An important question for future studies is, therefore, whether NHE1 and NBCn1 simply serve to regulate global tumor cell pH i or they additionally play specialized roles, e.g. in the form of localized subcellular pH i regulation or specific effects on signaling events.…”

Section: Discussionmentioning

confidence: 99%

The net acid extruders NHE1, NBCn1 and MCT4 promote mammary tumor growth through distinct but overlapping mechanisms

Andersen

Samsøe-Petersen

Oernbo

et al. 2018

Intl Journal of Cancer

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High metabolic and proliferative rates in cancer cells lead to production of large amounts of H and CO , and as a result, net acid extruding transporters are essential for the function and survival of cancer cells. We assessed protein expression of the Na /H exchanger NHE1, the Na - HCO3- cotransporter NBCn1, and the lactate-H cotransporters MCT1 and -4 by immunohistochemical analysis of a large cohort of breast cancer samples. We found robust expression of these transporters in 20, 10, 4 and 11% of samples, respectively. NHE1 and NBCn1 expression both correlated positively with progesterone receptor status, NHE1 correlated negatively and NBCn1 positively with HER2 status, whereas MCT4 expression correlated with lymph node status. Stable shRNA-mediated knockdown (KD) of either NHE1 or NBCn1 in the MDA-MB-231 triple-negative breast cancer (TNBC) cell line significantly reduced steady-state intracellular pH (pH ) and capacity for pH recovery after an acid load. Importantly, KD of any of the three transporters reduced in vivo primary tumor growth of MDA-MB-231 xenografts. However, whereas KD of NBCn1 or MCT4 increased tumor-free survival and decreased in vitro proliferation rate and colony growth in soft agar, KD of NHE1 did not have these effects. Moreover, only MCT4 KD reduced Akt kinase activity, PARP and CD147 expression and cell motility. This work reveals that different types of net acid extruding transporters, NHE1, NBCn1 and MCT4, are frequently expressed in patient mammary tumor tissue and demonstrates for the first time that they promote growth of TNBC human mammary tumors in vivo via distinct but overlapping mechanisms.

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Section: Discussionmentioning

confidence: 99%

The net acid extruders NHE1, NBCn1 and MCT4 promote mammary tumor growth through distinct but overlapping mechanisms

Andersen

Samsøe-Petersen

Oernbo

et al. 2018

Intl Journal of Cancer

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“…Examples of kinase-mediated activators of NHE1 include: extracellular signal regulated kinases ERK1/2 which are important in the activation of NHE1 in response to intracellular acidosis, and for which NHE1 serves as a signal scaffold (54,55); AKT (protein kinase B) which activates NHE1 in response to insulin and platelet-derived growth factor in fibroblasts (56), but inhibits NHE1 activity in cardiomyocytes (57); -Raf which phosphorylates NHE1 at amino acid threonine 653 (58); and p90 ribosomal S6 kinase (p90 RSK ) which phosphorylates NHE1 at serine 703, activating the exchanger in response to serum (59). Adaptor protein 14-3-3 binds NHE1 at the phosphorylated serine 703 residue and prevents its dephosphorylation (60).…”

Section: Nhe1: the Major Cellular Regulator Of Ph Homeostasismentioning

confidence: 99%

Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

Amith

Fliegel

2017

Seminars in Cancer Biology

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Please cite this article as: Amith Schammim Ray, Fliegel Larry.Na+/H+ exchangermediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics.Seminars in Cancer Biology http://dx.doi. org/10.1016/j.semcancer.2017.01.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Abstract (250 words):Breast cancer is the leading cause of cancer-related death in women in Europe and North America, and metastasis is the primary cause of fatality in patients with breast cancer. While some breast cancers are quite treatable, the triple-negative breast cancers are more metastatic and resistant to chemotherapy. There is clearly an urgent need for better treatments for this form of the disease. Breast cancer is characterized by genetically complex intra-tumour heterogeneity, particularly within the triple-negative clinical subtype. This complicates treatment options, so the development of specifically targeted chemotherapy for less treatable forms is critical.Dysregulation of pH homeostasis is a common factor in breast tumour cells. This occurs in concert with a metabolic switch to aerobic glycolysis that occurs at the onset of oncogenic transformation. The Na + /H + exchanger isoform 1 (NHE1) is the major pH regulatory protein involved in the increased proton extrusion of breast cancer cells. Its increased activity results in intracellular alkalinisation and extracellular acidification that drives cancer progression. The acidification of the extracellular tumour microenvironment also contributes to the development of chemotherapy resistance. In this review, we outline the role of H + as a carcinogenic signal and the role and regulation of NHE1 as a trigger for metastasis. We review recent evidence supporting the use of pharmacological inhibitors of NHE1 as a viable treatment option for triplenegative breast cancer.

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“…with NHE1 (28). Therefore, NHE1 activation due to LSSinduced dephosphorylation of AMPK-Thr172 could be mediated by either ERK1/2 or CD44.…”

Section: Discussionmentioning

confidence: 97%

AMP‐activated protein kinase regulates glycocalyx impairment and macrophage recruitment in response to low shear stress

et al. 2019

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Low shear stress (LSS) increases degradation of the endothelial glycocalyx, leading to production of endothelial inflammation and atherosclerosis. However, the underlying mechanisms of how LSS diminishes the endothelial glycocalyx remain unclear. We showed that LSS inactivated AMPK, enhanced Na+‐H+ exchanger (NHE)1 activity, and induced glycocalyx degradation. Activation of AMPK prevented LSS‐induced NHE1 activity and endothelial glycocalyx impairment. We further identified hyaluronidase 2 (HYAL2) as a mediator of endothelial glycocalyx impairment in HUVECs exposed to LSS. Inactivation of AMPK by LSS up‐regulates the activity of HYAL2, which acts downstream of NHE1. We characterized a left common carotid artery partial ligation (PL) model of LSS in C57BL/6 mice. The results showed decreased expression of hyaluronan (HA) in the endothelial glycocalyx and decreased thickness of the endothelial glycocalyx in PL mice. Pharmacological activation of AMPK by ampkinone not only attenuated glycocalyx impairment due to HA degradation but also blocked vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 expression increase and macrophage recruitment in the endothelia of PL mice. Our results revealed that AMPK dephosphorylation induced by LSS activates NHE1 and HYAL2 to promote HA degradation and glycocalyx injury, which may contribute to endothelial inflammatory reaction and macrophage recruitment.—Zhang, J., Kong, X., Wang, Z., Gao, X., Ge, Z., Gu, Y., Ye, P., Chao, Y., Zhu, L., Li, X., Chen, S. AMP‐activated protein kinase regulates glycocalyx impairment and macrophage recruitment in response to low shear stress. FASEB J. 33, 7202–7212 (2019). http://www.fasebj.org

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The human Na+/H+ exchanger 1 is a membrane scaffold protein for extracellular signal-regulated kinase 2

Cited by 51 publications

References 83 publications

The net acid extruders NHE1, NBCn1 and MCT4 promote mammary tumor growth through distinct but overlapping mechanisms

The net acid extruders NHE1, NBCn1 and MCT4 promote mammary tumor growth through distinct but overlapping mechanisms

Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

AMP‐activated protein kinase regulates glycocalyx impairment and macrophage recruitment in response to low shear stress

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