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

Abstract

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.

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

“…Taken together, our analysis (>1000 glioma cases) strongly suggests that NHE1 protein is involved in glioma tumorigenesis and progression. The underlying mechanisms could include promoting tumor proliferation and invasion [ 37 – 41 ]. Our gene ontology analysis indicates that NHE1 protein is involved in the tumor migration and invasion by the regulation of cell adhesion and extracellular matrix organization.…”

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

“…In human hepatocarcinoma cells it was demonstrated that IL-6 induces cell migration and invasiveness, mediated by facilitating the interaction of NHE1 and CaM, forming a molecular complex with enhanced transport activity that regulates intracellular pH and Ca 2+ concentration [304]. In contrast to what happens in other cells, stimulation of NHE1 by angiotensin-II, due to cytosolic Ca 2+ increase and subsequent CaM activation, induced the repression of melanoma cell migration, a process that was mirrored by losartan, an inhibitor of the angiotensin-II receptor type 1 (AT 1 ) while promoting the adhesion and invasiveness of these tumor cells [305].…”

Drug-Induced Melanoma: Irbesartan Induced Cutaneous Melanoma! First Description in the World Literature!

“…The number of studies, according to which different groups of antihypertensive drugs are likely to potentiate the development of melanoma, increases significantly [1], [2], [3]. According to the literature, angiotensin receptor blockers (ARBs), which are widely used as antihypertensive drugs, carry an increased risk of developing cancer [4].…”