Protease activity at invadopodial focal digestive areas is dependent on NHE1-driven acidic pHe

Greco, Maria Raffaella; Antelmi, Ester; Busco, Giovanni; Guerra, Lorenzo; Rubino, Rosa; Casavola, Valeria; Reshkin, Stephan J.; Cardone, Rosa Angela

doi:10.3892/or.2013.2923

Cited by 66 publications

(54 citation statements)

References 27 publications

(35 reference statements)

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“…ATII does stimulate the expression and activity of MMPs, as shown for, among others, MMP2 and MMP13, in murine melanoma (B16F10) cells [38] and MMP2 in human melanoma cells [39]. Even the ATII-stimulated NHE1 activity alone might enhance invasion because the resulting local acidification at the cell surface promotes protease activity [40, 41]. We conclude that not only the ATII-stimulated NHE1 activity, but also an interplay of various effects, including ATII-triggered increase of MMP activity, and possibly ATII-mediated activation of angiotensin converting enzyme (ACE) may play a significant role in promoting adhesion and invasion.…”

Section: Discussionmentioning

confidence: 99%

The Angiotensin II Type 1 Receptor Antagonist Losartan Affects NHE1-Dependent Melanoma Cell Behavior

Hofschröer

Nielsen

et al. 2018

Cell Physiol Biochem

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Background/Aims: The peptide hormone angiotensin II (ATII) plays a prominent role in regulating vasoconstriction and blood pressure. Its primary target is the angiotensin II receptor type 1 (AT₁), the stimulation of which induces an increase in cytosolic [Ca²⁺] and calmodulin activation. Ca²⁺-bound (activated) calmodulin stimulates the activity of the Na⁺/ H⁺ exchanger isoform 1 (NHE1); and increased NHE1 activity is known to promote melanoma cell motility. The competitive AT₁ receptor inhibitor losartan is often used to lower blood pressure in hypertensive patients. Since AT₁ mediates ATII-stimulated NHE1 activity, we set out to investigate whether ATII and losartan have an impact on NHE1-dependent behavior of human melanoma (MV3) cells. Methods: ATII receptor expression was verified by PCR, F-actin was visualized using fluorescently labeled phalloidin, and cytosolic [Ca²⁺] and pH were determined ratiometrically using Fura-2 and BCECF, respectively. MV3 cell behavior was analyzed using migration, adhesion, invasion and proliferation assays. Results: MV3 cells express both AT₁ and the angiotensin II receptor type 2 (AT₂). Stimulation of MV3 cells with ATII increased NHE1 activity which could be counteracted by both losartan and the Ca²⁺/ calmodulin inhibitor ophiobolin-A. ATII stimulation induced a decrease in MV3 cell migration and a more spherical cell morphology accompanied by an increase in the density of F-actin. Independently of the presence of ATII, both NHE1 and migratory activity were reduced when AT₁ was blocked by losartan. On the other hand, losartan clearly increased cell adhesion to, and the invasion of, a collagen type I substrate. The AT₂ inhibitor PD123319 did not affect NHE1 activity, proliferation and migration, but increased adhesion and invasion. Conclusion: Losartan inhibits NHE1 activity and the migration of human melanoma cells. At the same time, losartan promotes MV3 cell adhesion and invasion. The therapeutic use of AT₁ antagonists (sartans) in hypertensive cancer patients should therefore be given critical consideration.

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Section: Discussionmentioning

confidence: 99%

The Angiotensin II Type 1 Receptor Antagonist Losartan Affects NHE1-Dependent Melanoma Cell Behavior

Hofschröer

Nielsen

et al. 2018

Cell Physiol Biochem

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“…NHE1 activity acidifies the peri-invadopodial space, establishing the optimal pH for the proteolytic activity of serine proteases and matrix metalloproteinases that aid in the digestion of extracellular matrix at the leading edge of invading cells (75,76) Of all the mutations to NHE1, though, S703A was the most remarkable. Cells expressing S703A-NHE1 exhibited a drastic change in morphology, seemingly reverting from their characteristic mesenchymal morphology to a more epithelial-like phenotype.…”

Section: Beyond "Housekeeping": Nhe1's Definitive Role In Triple-negamentioning

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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“…However, many proteinases are secreted at invadopodia and could collaborate to promote degradation of ECM in tissues. These proteinases include MT1-MMP, MMP-2, MMP-9, seprase, cathepsin B, ADAM12, and uPAR [27, 28, 44, 46-50]. Some of these proteinases are also likely to activate latent ECM- and cell-associated growth factors [51-56].…”

Section: Introductionmentioning

confidence: 99%

Regulation of invadopodia by mechanical signaling

Parekh

Weaver

2016

Experimental Cell Research

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Mechanical rigidity in the tumor microenvironment is associated with a high risk of tumor formation and aggressiveness. Adhesion-based signaling driven by a rigid microenvironment is thought to facilitate invasion and migration of cancer cells away from primary tumors. Proteolytic degradation of extracellular matrix (ECM) is a key component of this process and is mediated by subcellular actin-rich structures known as invadopodia. Both ECM rigidity and cellular traction stresses promote invadopodia formation and activity, suggesting a role for these structures in mechanosensing. The presence and activity of mechanosensitive adhesive and signaling components at invadopodia further indicates the potential for these structures to utilize myosin-dependent forces to probe and remodel their ECM environments. Here, we provide a brief review of the role of adhesion-based mechanical signaling in controlling invadopodia and invasive cancer behavior.

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Protease activity at invadopodial focal digestive areas is dependent on NHE1-driven acidic pHe

Cited by 66 publications

References 27 publications

The Angiotensin II Type 1 Receptor Antagonist Losartan Affects NHE1-Dependent Melanoma Cell Behavior

The Angiotensin II Type 1 Receptor Antagonist Losartan Affects NHE1-Dependent Melanoma Cell Behavior

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

Regulation of invadopodia by mechanical signaling

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