Down-regulation of Na + /H + exchanger 1 by Toll-like receptor stimulation in macrophages

Takakuwa, Shiho; Mizuno, Natsumi; Takano, T.; Asakawa, Shuichi; Sato, Taiki; Hiratsuka, Masahiro; Hirasawa, Noriyasu

doi:10.1016/j.imbio.2016.10.005

Cited by 4 publications

(4 citation statements)

References 42 publications

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“…The alternative M2 phenotype of macrophages are suggested to promote the progression of tumor, compared with the pro-inflammatory M1 phenotype of macrophages [ 53 ]. It has been reported that lipopolysaccharide (LPS), a ligand of Toll-like receptor (TLR), alters the phenotype of tumor-associated macrophages from M2 to M1 via regulation of NHE1 protein expression in macrophages [ 54 , 55 ]. In our study, HOE642 treatment inhibited stimulation of M2 phenotypes of TAMs by reducing protumoral CD206 + TAMs in both resident microglia TAMs and peripheral TAMs ( p < 0.05, Fig.…”

Section: Discussionmentioning

confidence: 99%

Elevated Na/H exchanger 1 (SLC9A1) emerges as a marker for tumorigenesis and prognosis in gliomas

Guan

Luo

Begum

et al. 2018

J Exp Clin Cancer Res

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BackgroundSodium/hydrogen exchanger 1 (NHE1), encoded by the SLC9A1 gene (SoLute Carrier family 9A1) in humans, is the main H+ efflux mechanism in maintaining alkaline intracellular pH (pHi) and Warburg effects in glioma. However, to date, there are no clinical studies exploring pharmacological inhibition of NHE1 protein in cancer treatment. In this study, we investigated NHE1 expression in gliomas and its relationship with glioma clinical outcome.MethodsThe Chinese Glioma Genome Atlas (CGGA) dataset containing transcriptome sequencing data of 325 glioma samples and the Cancer Genome Atlas (TCGA) with 698 glioma mRNAseq data were analyzed in this study. Mouse SB28 and GL26 intracranial syngeneic glioma models in C57BL/6 J mice were established to investigate NHE1 expression and impact of NHE1 protein inhibition with its inhibitor HOE642 on tumorigenesis and anti-PD1 therapy. Tumor angiogenesis, immunogenicity, and progression were assessed by immunofluorescence staining and flow cytometric profiling.ResultsAnalysis of SLC9A1 mRNA expression in two data sets, CGGA and TCGA, reveals significantly higher SLC9A1 mRNA levels in higher grade gliomas. The SLC9A1 mRNA expression was especially enriched in isocitrate dehydrogenase (IDH)1/2 wild-type glioblastoma (GBM) and in mesenchymal glioma subtypes. Worsened survival probabilities were correlated with the elevated SLC9A1 mRNA levels in gliomas. The underlying mechanisms include promoting angiogenesis, and extracellular matrix remodeling. Increased SLC9A1 mRNA expression was also associated with tumor-associated macrophage accumulation. NHE1 inhibitor HOE642 reduced glioma volume, invasion, and prolonged overall survival in mouse glioma models. Blockade of NHE1 protein also stimulated immunogenic tumor microenvironment via activating CD8 T-cell accumulation, increasing expression of interferon-gamma (Ifng), and sensitized animals to anti-PD-1 therapy.ConclusionOur findings strongly suggest that NHE1 protein emerges as a marker for tumorigenesis and prognosis in glioma. Blocking NHE1 protein is a novel strategy for adjuvant anti-cancer therapies.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0923-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Elevated Na/H exchanger 1 (SLC9A1) emerges as a marker for tumorigenesis and prognosis in gliomas

Guan

Luo

Begum

et al. 2018

J Exp Clin Cancer Res

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“…NHE‐1 is ubiquitously expressed in mammalian cells, at different extents, 13 and is modulated by stress 40,41 . In both 4T1 and TS/A tumor models, not only tumor cells, but also M2 macrophages express significantly NHE‐1, whereas endothelial cells are negative.…”

Section: Discussionmentioning

confidence: 99%

“…NHE‐1 is ubiquitously expressed in mammalian cells, at different extents, 13 and is modulated by stress. 40 , 41 In both 4T1 and TS/A tumor models, not only tumor cells, but also M2 macrophages express significantly NHE‐1, whereas endothelial cells are negative. Therefore, EIPA is likely to act directly on infiltrating myeloid cells that express NHE‐1, but indirectly on vessels cells, whose decrease may be secondary to the effects of the combo treatment on the tumor.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic efficacy of proton transport inhibitors alone or in combination with cisplatin in triple negative and hormone sensitive breast cancer models

et al. 2021

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Triple negative breast cancers (TNBCs) are very aggressive and have a poor prognosis due to lack of efficacious therapies. The only effective treatment is chemotherapy that however is frequently hindered by the occurrence of drug resistance. We approached this problem in vitro and in vivo on a triple negative and a hormone sensitive breast cancer cell lines: 4T1 and TS/A. A main defense mechanism of tumors is the extrusion of intracellular protons derived from the metabolic shift to glycolysis, and necessary to maintain an intracellular pH compatible with life. The resulting acidic extracellular milieu bursts the malignant behavior of tumors and impairs chemotherapy. Therefore, we investigated the efficacy of combined therapies that associate cisplatin (Cis) with proton exchanger inhibitors, such as esomeprazole (ESO) and 5‐(N‐ethyl‐N‐isopropyl)amiloride (EIPA). Our results demonstrate that in the 4T1 triple negative model the combined therapy Cis plus EIPA is significantly more effective than the other treatments. Instead, in the TS/A tumor the best therapeutic result is obtained with ESO alone. Remarkably, in both 4T1 and TS/A tumors these treatments correlate with increase of CD8+ T lymphocytes and dendritic cells, and a dramatic reduction of M2 macrophages and other suppressor myeloid cells (MDSC) in the tumor infiltrates.

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“…A study examined NHE1 expression in macrophages of inflammatory diseases. Long-term inflammatory stimulation, such as LPS exposure, can activate TLR4 on intestinal macrophages, leading to inflammation through the MYD88-dependent pathway, thereby accelerating intracellular degranulation of NHE1 mediated by the ubiquitin-proteasome system (65).…”

Section: Proton (H + ) Transportersmentioning

confidence: 99%

Uncovering the interplay between pH receptors and immune cells: Potential drug targets (Review)

et al. 2021

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Extracellular acidosis is associated with various immunopathological states. The microenvironment of numerous solid tumours and inflammatory responses during acute or chronic infection are all related to a pH range of 5.5-7.0. The relationship between inflammation and immune escape, cancer metabolism, and immunologic suppression drives researchers to focus on the effects of low pH on diverse components of disease immune monitoring. The potential effect of low extracellular pH on the immune function reveals the importance of pH in inflammatory and immunoreactive processes. In this review, the mechanism of how pH receptors, including monocarboxylate transporters (MCTs), Na + /H + exchanger 1, carbonic anhydrases (CAs), vacuolar-ATPase, and proton-sensing G-protein coupled receptors (GPCRs), modulate the immune system in disease, especially in cancer, were studied. Their role in immunocyte growth and signal transduction as part of the immune response, as well as cytokine production, have been documented in great detail. Currently, immunotherapy strategies have positive therapeutic effects for patients. However, the acidic microenvironment may block the effect of immunotherapy through compensatory feedback mechanisms, leading to drug resistance. Therefore, we highlight promising therapeutic developments regarding pH manipulation and provide a framework for future research.

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Down-regulation of Na + /H + exchanger 1 by Toll-like receptor stimulation in macrophages

Cited by 4 publications

References 42 publications

Elevated Na/H exchanger 1 (SLC9A1) emerges as a marker for tumorigenesis and prognosis in gliomas

Elevated Na/H exchanger 1 (SLC9A1) emerges as a marker for tumorigenesis and prognosis in gliomas

Therapeutic efficacy of proton transport inhibitors alone or in combination with cisplatin in triple negative and hormone sensitive breast cancer models

Uncovering the interplay between pH receptors and immune cells: Potential drug targets (Review)

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