KR-33028, a potent inhibitor of the Na+/H+ exchanger NHE1, suppresses metastatic potential of triple-negative breast cancer cells

Amith, Schammim Ray; Wilkinson, Jodi Marie; Fliegel, Larry

doi:10.1016/j.bcp.2016.08.010

Cited by 32 publications

(18 citation statements)

References 28 publications

(54 reference statements)

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“…Importantly, constitutive increases in pH i have been linked to increased migration in cancer cell models (Amith et al, 2015(Amith et al, , 2016aParks and Pouyssegur, 2015;Lin et al, 2012;Cong et al, 2014), and we have recently shown that increased pH i enables cancer cell invasion in an animal model (Grillo-Hill et al, 2015). Importantly, in these studies, decreasing pH i inhibits the migration or invasion phenotype, suggesting that lowering the pH i of cancer cells as part of cancer therapy can limit metastasis.…”

Section: Migration and Metastasismentioning

confidence: 78%

“…Supporting this idea, lowering pH i through genetic knockdown or inhibition of ion transporters reduces cell proliferation and migration Amith et al, 2016a;Le Floch et al, 2011), cell invasion (Yang et al, 2010), and suppresses tumorigenesis in xenograft models (Amith et al, 2015;Lagarde et al, 1988;Sonveaux et al, 2008;Colen et al, 2011;Chiche et al, 2012). Additionally, we have recently shown in Drosophila animal models and human clonal cells that, by lowering the pH i , we can induce synthetic lethality with expression of activated oncogenes -notably Raf and Raspossibly by limiting the efflux of metabolically generated acids (Grillo-Hill et al, 2015).…”

Section: Tumorigenesismentioning

confidence: 94%

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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: Migration and Metastasismentioning

confidence: 78%

Section: Tumorigenesismentioning

confidence: 94%

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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“…The Na + /H + -exchanger 1 (NHE1) binds Ca 2+ /CaM at its C-terminal region preventing auto-inhibition, and upregulation of this transport system plays an important role in EMT and metastasis development in triple-negative human breast carcinoma, a process that is inhibited by a specific NHE1 inhibitor [302,303]. CaM plays an important role in this process, as cells expressing a NHE1 with a mutation of the CaM-binding site that yields a constitutive active protein, showed enhanced migration, invasion, and spheroid growth, suggesting an increase of the metastatic potential of these carcinomas [302].…”

Section: Other Cam-binding Proteinsmentioning

confidence: 99%

The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

Villalobo

Berchtold

2020

IJMS

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Calmodulin (CaM) is the principal Ca2+ sensor protein in all eukaryotic cells, that upon binding to target proteins transduces signals encoded by global or subcellular-specific changes of Ca2+ concentration within the cell. The Ca2+/CaM complex as well as Ca2+-free CaM modulate the activity of a vast number of enzymes, channels, signaling, adaptor and structural proteins, and hence the functionality of implicated signaling pathways, which control multiple cellular functions. A basic and important cellular function controlled by CaM in various ways is cell motility. Here we discuss the role of CaM-dependent systems involved in cell migration, tumor cell invasiveness, and metastasis development. Emphasis is given to phosphorylation/dephosphorylation events catalyzed by myosin light-chain kinase, CaM-dependent kinase-II, as well as other CaM-dependent kinases, and the CaM-dependent phosphatase calcineurin. In addition, the role of the CaM-regulated small GTPases Rac1 and Cdc42 (cell division cycle protein 42) as well as CaM-binding adaptor/scaffold proteins such as Grb7 (growth factor receptor bound protein 7), IQGAP (IQ motif containing GTPase activating protein) and AKAP12 (A kinase anchoring protein 12) will be reviewed. CaM-regulated mechanisms in cancer cells responsible for their greater migratory capacity compared to non-malignant cells, invasion of adjacent normal tissues and their systemic dissemination will be discussed, including closely linked processes such as the epithelial–mesenchymal transition and the activation of metalloproteases. This review covers as well the role of CaM in establishing metastatic foci in distant organs. Finally, the use of CaM antagonists and other blocking techniques to downregulate CaM-dependent systems aimed at preventing cancer cell invasiveness and metastasis development will be outlined.

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“…We have recently tested a new, more selective and potent NHE1 inhibitor, KR-33028, (88) in MDA-MB-231, MDA-MB-468, and Hs578T cells, which are representative of multiple TNBC subtypes. It was very effective in reducing rates of migration, invasion and clonogenic colony growth, all of which are characteristics that are predictive of metastasis in patients, A related approach to decrease NHE1 activity is to affect NHE1 regulation.…”

Section: Nhe1 Inhibition As a Chemotherapy Strategy: The Challenge Ofmentioning

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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KR-33028, a potent inhibitor of the Na+/H+ exchanger NHE1, suppresses metastatic potential of triple-negative breast cancer cells

Cited by 32 publications

References 28 publications

Cancer cell behaviors mediated by dysregulated pH dynamics at a glance

Cancer cell behaviors mediated by dysregulated pH dynamics at a glance

The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

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

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