NHE1 mediates MDA-MB-231 cells invasion through the regulation of MT1-MMP

Lin, Yani; Chang, Guoqiang; Wang, Jian; Jin, Wei‐Na; Wang, Lihong; Li, Huawen; Ma, Li; Li, Qinghua; Pang, Tianxiang

doi:10.1016/j.yexcr.2011.05.026

Cited by 52 publications

(50 citation statements)

References 36 publications

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“…Interestingly, we have shown in this study that NHE7-overexpression facilitates tumor invasion, cell-overlay and tumor formation in vivo. NHE1 is known to facilitate tumor invasion by acidifying the local pH and thereby activating pH-sensitive enzymes that degrade the extracellular matrix (9, [40][41][42][43][44][45]. In agreement, we also showed that overexpression of NHE1 in MDA-MB-231 cells enhances cell invasion (N1 in Fig.…”

Section: Discussionsupporting

confidence: 82%

Organellar (Na+, K+)/H+ exchanger NHE7 regulates cell adhesion, invasion and anchorage-independent growth of breast cancer MDA-MB-231 cells

Onishi

Lin²,

Numata³

et al. 2011

Oncol Rep

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Abstract. Na+ /H + exchangers (NHEs) are a group of secondary active antiporters that regulate cellular pH, cell volume and ion homeostasis. In humans, nine isoforms (NHE1-NHE9) were identified and characterized as functional NHEs. While a growing body of evidence indicates that NHE1 generates an acidic tumor environment and thereby contributes to tumor invasion, little is known about the role of other NHE isoforms in tumor progression. NHE7 is a unique member of the NHE gene family that dynamically shuttles between the trans-Golgi network, endosomes and the plasma membrane, and regulates the luminal pH of these organelles. Here we show that NHE7-overexpression in breast cancer MDA-MB-231 cells enhances cell overlay, cell-cell adhesion, invasion, anchorage-independent tumor growth and tumor formation in vivo. In contrast, NHE1-overexpression enhances tumor invasion, but it has little effect on cell adhesion or anchorageindependent tumor growth. Pathological examinations of the tumor samples derived from NHE7-overexpressing cells showed a similar appearance to aggressive tumors. Together, these results suggest that NHE7 enhances tumor progression. This is the first report to show the involvement of an organellar NHE in oncogenic processes.

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Section: Discussionsupporting

confidence: 82%

Organellar (Na+, K+)/H+ exchanger NHE7 regulates cell adhesion, invasion and anchorage-independent growth of breast cancer MDA-MB-231 cells

Onishi

Lin²,

Numata³

et al. 2011

Oncol Rep

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“…In breast cancer cells, NHE1 activity increases expression of MMP2 stimulator membrane type 1 MMP via ERK1/2 and p38 mitogen-activated protein kinase signaling pathways (46). NHE1 and ERK1/2 signaling activations are also involved in fibronectin-induced enhancement of MMP2 and F-actin expression and cell migration (31).…”

Section: Nhe1 In Gbmmentioning

confidence: 99%

Upregulation of NHE1 protein expression enables glioblastoma cells to escape TMZ-mediated toxicity via increased H⁺extrusion, cell migration and survival

Cong

Zhu

Shi

et al. 2014

CARCIN

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Sodium-hydrogen exchanger isoform 1 (NHE1) plays a role in survival and migration/invasion of several cancers and is an emerging new therapeutic target. However, the role of NHE1 in glioblastoma and the interaction of NHE1 expression and function in glioblastoma cells with cytotoxic temozolomide (TMZ) therapy remain unknown. In this study, we detected high levels of NHE1 protein only in primary human glioma cells (GC), glioma xenografts and glioblastoma, but not in human neural stem cells or astrocytes. GC exhibited an alkaline resting pH i (7.46 ± 0.04) maintained by robust NHE1-mediated H + extrusion. GC treatment with TMZ for 2-24 h triggered a transient decrease in pH i , which recovered by 48 h and correlated with concurrent upregulation of NHE1 protein expression. NHE1 protein was colocalized with ezrin at lamellipodia and probably involved in GC migration. The TMZ-treated GC exhibited increased migration and invasion, which was attenuated by addition of NHE1 inhibitor HOE-642. Most importantly, NHE1 inhibition prevented prosurvival extracellular signal-regulated kinase activation and accelerated TMZ-induced apoptosis. Taken together, our study provides the first evidence that GC upregulate NHE1 protein to maintain alkaline pH i . Combining TMZ therapy with NHE1 inhibition suppresses GC migration and invasion, and also augments TMZ-induced apoptosis. These findings strongly suggest that NHE1 is an important cytoprotective mechanism in GC and presents a new therapeutic strategy of combining NHE1 inhibition and TMZ chemotherapy.

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“…Acidic extracellular pH increases MMP-9 expression, and pharmacological inhibition of NHE-1 downregulates MT1-MMP, a key activator of MMP-2. 105,106 Intracellular trafficking via lyosomes and vesicles targets these proteases to invadopodia, a process that is dependent upon tumor microenvironmental pH. 107,108 In prostate cancer cells, NHE-1 activity promotes lysosomal fusion to invadopodia; these lysosomes then release cathepsin B to facilitate ECM proteolysis.…”

Section: Growth Factorsmentioning

confidence: 99%

Regulation of invadopodia by the tumor microenvironment

Gould

Courtneidge

2014

Cell Adhesion & Migration

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NHE1 mediates MDA-MB-231 cells invasion through the regulation of MT1-MMP

Cited by 52 publications

References 36 publications

Organellar (Na+, K+)/H+ exchanger NHE7 regulates cell adhesion, invasion and anchorage-independent growth of breast cancer MDA-MB-231 cells

Organellar (Na+, K+)/H+ exchanger NHE7 regulates cell adhesion, invasion and anchorage-independent growth of breast cancer MDA-MB-231 cells

Upregulation of NHE1 protein expression enables glioblastoma cells to escape TMZ-mediated toxicity via increased H⁺extrusion, cell migration and survival

Regulation of invadopodia by the tumor microenvironment

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NHE1 mediates MDA-MB-231 cells invasion through the regulation of MT1-MMP

Cited by 52 publications

References 36 publications

Organellar (Na+, K+)/H+ exchanger NHE7 regulates cell adhesion, invasion and anchorage-independent growth of breast cancer MDA-MB-231 cells

Organellar (Na+, K+)/H+ exchanger NHE7 regulates cell adhesion, invasion and anchorage-independent growth of breast cancer MDA-MB-231 cells

Upregulation of NHE1 protein expression enables glioblastoma cells to escape TMZ-mediated toxicity via increased H+extrusion, cell migration and survival

Regulation of invadopodia by the tumor microenvironment

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Upregulation of NHE1 protein expression enables glioblastoma cells to escape TMZ-mediated toxicity via increased H⁺extrusion, cell migration and survival