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

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.

LncRNA LINC00662 promotes colon cancer tumor growth and metastasis by competitively binding with miR-340-5p to regulate CLDN8/IL22 co-expression and activating ERK signaling pathway

“…In the patients with advanced colon cancer, the defects of the above therapy are obvious resulting in a poor prognosis. Postoperative metastasis for colon cancer chiefly includes hematological metastasis, peritoneal metastasis and distant lymph node metastasis, which are frequently accompanied by local recurrence [4]. Hematogenous metastasis is the dominating cause of failure in the treatment of colon cancer.…”

Renin-Angiotensin System in Lung Tumor and Microenvironment Interactions

“…Ang II increased the phosphorylation of the extracellular signal-regulated protein kinase 1/2, c-jun-N-terminal kinase 1/2, or p38 mitogen-activated protein kinases, signaling pathways involved on cell proliferation and particularly relevant for cancer development [67,68] (Figure 2). Notably, in fibroblasts, Ang II binding to AT1R results in Smad2 and Smad3 phosphorylation via the ERK/p38/MAPK pathway, increasing the activation of the TGFβ1/Smad2/Smad3/Smad4 signaling [69]. Telmisartan, an AT1 receptor antagonist, significantly inhibited the growth of the non-small cell lung cancer (NSCLC) A549 cell line, in a time-and dose-dependent manner and led to an increase of the pro-apoptotic proteins caspase-3 and Bcl-xL [70].…”

“…Notably, nanoparticle-based AT2 receptor gene transfection, which markedly increased AT2 receptor expression, resulted in increased cell death of the human lung cancer cell line A549 [81]. The activation of AT2 receptor signaling has been described to produce antiproliferative, survival-promoting, as well as migratory, pro-invasive effects due to phosphatase-mediated (phosphotyrosine phosphatase PTP, protein tyrosine phosphatase 1B, PTP1B, and protein phosphatase 2A, PP2A) dephosphorylating events, through an inhibitory effect on Ras and MEK1/2 proteins of the Smad and MAPK pathways (PTP and PP2A) and by PTP1B-mediated novel Caveolin-1 (CAV1) dephosphorylation and inhibition of the CAV1/Rab5/Rac-1 pathway [69,85] (Figure 2).…”

The role of the renin‐angiotensin system in skin physiology and pathophysiology

“…The B16/ F10 mouse melanoma cell line is an exception and possesses only AT 2 Rs. [68][69][70][71] Normal melanocytes express exclusively AT 1 Rs. [2,69]…”

“…[ 69 ] However, even though this study provided a whole set of data, which consistently supported the authors’ conclusions, the more common notion on the role of angiotensin receptors in cancer in the scientific literature is that the AT 1 R acts pro‐proliferative, while the AT 2 R is a tumor suppressor that inhibits proliferation, migration and metastasis. [ 72,73 ] In fact, another very recent study by Martinez‐Meza et al [ 71 ] reported that selective stimulation or overexpression of AT 2 Rs in mouse B16/F10 and human A375 melanoma cells reduced “normal” and transendothelial migration. The view that AT 2 Rs have anti‐cancer effects is supported by the fact that an AT 2 R‐binding protein, ATIP (also termed MTUS) has been identified to be a tumor suppressor protein.…”