Angiotensin-(1–1) Suppresses Hepatocellular Carcinoma Growth and Angiogenesis via Complex Interactions of Angiotensin II Type 1 Receptor, Angiotensin II Type 2 Receptor and Mas Receptor

Liu, Yanping; Li, Bin; Wang, Ximing; Li, Guishuang; Shang, Rui; Yang, Jianmin; Wang, Jiali; Zhang, Meng; Chen, Yuguo; Zhang, Yun; Zhang, Cheng; Hao, Panpan

doi:10.2119/molmed.2015.00022

Cited by 45 publications

(31 citation statements)

References 59 publications

(64 reference statements)

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“…These observations are in keeping with the increase in ACE2 in chronic liver injuries in rats and humans (247,407) and with the liver steatosis associated with MAS-deficiencies in ApoE Ϫ/Ϫ mice (505). Other reports indicate that ANG-(1-7) suppresses the growth of hepatocellular carcinoma and angiogenesis via interactions of different angiotensin receptors (323).…”

Section: H Liversupporting

confidence: 75%

The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7)

Santos

Sampaio

Alzamora

et al. 2018

Physiological Reviews

821

893

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The renin-angiotensin system (RAS) is a key player in the control of the cardiovascular system and hydroelectrolyte balance, with an influence on organs and functions throughout the body. The classical view of this system saw it as a sequence of many enzymatic steps that culminate in the production of a single biologically active metabolite, the octapeptide angiotensin (ANG) II, by the angiotensin converting enzyme (ACE). The past two decades have revealed new functions for some of the intermediate products, beyond their roles as substrates along the classical route. They may be processed in alternative ways by enzymes such as the ACE homolog ACE2. One effect is to establish a second axis through ACE2/ANG-(1-7)/MAS, whose end point is the metabolite ANG-(1-7). ACE2 and other enzymes can form ANG-(1-7) directly or indirectly from either the decapeptide ANG I or from ANG II. In many cases, this second axis appears to counteract or modulate the effects of the classical axis. ANG-(1-7) itself acts on the receptor MAS to influence a range of mechanisms in the heart, kidney, brain, and other tissues. This review highlights the current knowledge about the roles of ANG-(1-7) in physiology and disease, with particular emphasis on the brain.

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Section: H Liversupporting

confidence: 75%

The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7)

Santos

Sampaio

Alzamora

et al. 2018

Physiological Reviews

821

893

View full text Add to dashboard Cite

show abstract

“…ACE2, Ang-(1-7) and Mas have the same signaling pathways. A recent study showed that Ang-(1-7) suppressed hepatocellular carcinoma growth and angiogenesis through inactivation of the p38 MAPK phosphorylation signaling pathway (21). Our previous study also demonstrated that Ang-(1-7) inhibited migration and invasion through the PI3K/Akt and MAPK signaling pathways (20).…”

Section: Discussionmentioning

confidence: 86%

ACE2 overexpression inhibits acquired platinum resistance-induced tumor angiogenesis in NSCLC

Cheng

Zhou

et al. 2016

Oncology Reports

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Angiotensin II (AngII) is a multifunctional bioactive peptide in the renin-angiotensin system (RAS). Angiotensin-converting enzyme 2 (ACE2) is a newly identified component of RAS. We previously reported that ACE2 overexpression may inhibit cell growth and vascular endothelial growth factor (VEGF) production in vitro and in vivo. In the present study, we investigated the effect of ACE2 on tumor-associated angiogen-esis after the development of acquired platinum resistance in non-small cell lung cancer (NSCLC). Four NSCLC cell lines, A549, LLC, A549-DDP and LLC-DDP, were used in vitro, while A549 and A549-DDP cells were used in vivo. A549-DDP and LLC-DDP cells were newly established at our institution as acquired platinum-resistant sublines by culturing the former parent cells in cisplatin (CDDP)-containing conditioned medium for 6 months. These platinum-resistant cells showed significantly higher angiotensin II type 1 receptor (AT1R), ACE and VEGF production and lower ACE2 expression than their corresponding parent cells. We showed that ACE2 overexpression inhibited the production of VEGF in vitro and in vivo compared to their corresponding parent cells. We also found that ACE2 overexpression reduced the expression of AT1R and ACE. Additionally, we confirmed that ACE2 overexpres-sion inhibited cell growth and VEGF production while simultaneously suppressing ACE and AT1R expression in human lung cancer xenografts. Our findings indicate that ACE2 overexpression may potentially suppress angiogenesis in NSCLC after the development of acquired platinum resistance.

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“…Furthermore, angiotensin II-AT1R signaling could also increase cell proliferation through cooperation with EGFR signaling [12]. In contrast, several previous studies demonstrated that AT1R expression was low and caused decreased or no significant regulation of cell growth in response to angiotensin II stimulation in some cancer cells [13–15]. Taken together, these results indicated that the role of angiotensin II-AT1R signaling in cell growth remains controversial and contradictory in a variety of human cancer cells.…”

Section: Discussionmentioning

confidence: 98%

Angiotensin II type I receptor (AT1R) is an independent prognosticator of esophageal squamous cell carcinoma and promotes cells proliferation via mTOR activation

Chang

et al. 2016

Oncotarget

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BackgroundThe aim of this study was to investigate the effects of the angiotensin II/ angiotensin II type I receptor (AT1R) and angiotensin II type II receptor (AT2R) signaling pathway in esophageal squamous cell carcinoma (ESCC).MethodsImmunohistochemistry was performed to evaluate the expression levels of AT1R and AT2R in tissues from 152 surgically resected ESCC patients, and those expression levels were then correlated with treatment outcomes. The angiotensin II/AT1R/AT2R signaling pathway and its biological effects in the context of ESCC were investigated in vitro and in vivo.ResultsIn human samples, AT1R overexpression was univariately associated with inferior overall survival and remained multivariately independent (hazard ratio=1.812). In vitro, angiotensin II stimulated the growth of ESCC cells in a dose-dependent manner. Treatment with irbesartan or AT1R-RNAi knockdown but not treatment with PD123319 significantly decreased the level of angiotensin II-induced ESCC cell proliferation. Angiotensin II also caused mTOR activation in a dose-dependent manner, and everolimus or mTOR-RNAi knockdown significantly suppressed the level of angiotensin II-induced ESCC cell proliferation. Furthermore, AT1R-RNAi knockdown suppressed the activation of mTOR. Clinically, AT1R expression was also correlated with phosphorylated mTOR expression. In a xenograft model, local angiotensin II injection enhanced tumor growth, and this effect could be decreased by treatment with irbesartan or everolimus. In a 4-NQO-induced-ESCC murine model, irbesartan significantly decreased the incidence of esophageal tumor.ConclusionsThese findings suggest that AT1R overexpression is an independent adverse prognosticator for patients with ESCC and that angiotensin II/AT1R signaling stimulates ESCC growth, in part through mTOR activation.

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Angiotensin-(1–1) Suppresses Hepatocellular Carcinoma Growth and Angiogenesis via Complex Interactions of Angiotensin II Type 1 Receptor, Angiotensin II Type 2 Receptor and Mas Receptor

Cited by 45 publications

References 59 publications

The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7)

The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7)

ACE2 overexpression inhibits acquired platinum resistance-induced tumor angiogenesis in NSCLC

Angiotensin II type I receptor (AT1R) is an independent prognosticator of esophageal squamous cell carcinoma and promotes cells proliferation via mTOR activation

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