AT2 Receptor Mediated Activation of the Tyrosine Phosphatase PTP1B Blocks Caveolin-1 Enhanced Migration, Invasion and Metastasis of Cancer Cells.

Martínez-Meza Martínez-Meza,Lavandero Lavandero,Díaz-Valdivia Díaz-Valdivia,Ocaranza Ocaranza,Quest Quest,Rojas-Celis Rojas-Celis,Contreras Contreras,Chiong Chiong,Huilcaman Huilcaman,Sandoval-Bórquez Sandoval-Bórquez,Valenzuela-Valderrama Valenzuela-Valderrama,Díaz Díaz,Leyton Leyton

doi:10.3390/cancers11091299

Abstract

The renin–angiotensin receptor AT2R controls systemic blood pressure and is also suggested to modulate metastasis of cancer cells. However, in the latter case, the mechanisms involved downstream of AT2R remain to be defined. We recently described a novel Caveolin-1(CAV1)/Ras-related protein 5A (Rab5)/Ras-related C3 botulinum toxin substrate 1 (Rac1) signaling axis that promotes metastasis in melanoma, colon, and breast cancer cells. Here, we evaluated whether the anti-metastatic effect of AT2R is connected to inhibition of this pathway. We found that murine melanoma B16F10 cells expressed AT2R, while MDA-MB-231 human breast cancer cells did not. AT2R activation blocked migration, transendothelial migration, and metastasis of B16F10(cav-1) cells, and this effect was lost when AT2R was silenced. Additionally, AT2R activation reduced transendothelial migration of A375 human melanoma cells expressing CAV1. The relevance of AT2R was further underscored by showing that overexpression of the AT2R in MDA-MB-231 cells decreased migration. Moreover, AT2R activation increased non-receptor protein tyrosine phosphatase 1B (PTP1B) activity, decreased phosphorylation of CAV1 on tyrosine-14 as well as Rab5/Rac1 activity, and reduced lung metastasis of B16F10(cav-1) cells in C57BL/6 mice. Thus, AT2R activation reduces migration, invasion, and metastasis of cancer cells by PTP1B-mediated CAV1 dephosphorylation and inhibition of the CAV1/Rab5/Rac-1 pathway. In doing so, these observations open up interesting, novel therapeutic opportunities to treat metastatic cancer disease.

Highlights

The renin–angiotensin system plays a fundamental role in controlling vasoconstriction, cardiovascular function, and renal homeostasis [1]
We evaluated by western blotting AT2R expression in B16F10 murine melanoma and MDA-MB-231 human breast cancer cells
To determine if protein tyrosine phosphatase 1B (PTP1B) inhibited the CAV1/Rab5/related C3 botulinum toxin substrate 1 (Rac1) pathway, we evaluated the effect of the PTP1B inhibitor Cinn-GEL2-ME on

Summary

Introduction

The renin–angiotensin system plays a fundamental role in controlling vasoconstriction, cardiovascular function, and renal homeostasis [1]. Cancers 2019, 11, 1299 ligands for two of the relevant seven-transmembrane spanning G protein-coupled receptors, namely type. 1 (AT1R) and type 2 (AT2R) receptors. The antagonistic AT2R prevents these effects, mainly by activating phosphatases, such as SH2-containing protein tyrosine phosphatase-1 (SHP-1), MAPK phosphatase-1 (MKP-1), and protein phosphatase 2A (PP2A), which dephosphorylate effector proteins downstream of AT1R [4]. Expression of AT1R is fairly ubiquitous, while AT2R is mainly expressed during embryonic development and decreases in adult organisms [5]. In some pathological conditions, like cancer, both receptors are overexpressed [6] and participate in the control of cancer development [7]

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Conclusion