Hypoxia induces dysregulation of local renin-angiotensin system in mouse Lewis lung carcinoma cells

Fan, Li; Feng, Yanqin; Wan, Huanying; Ni, Lei; Qian, Yanrong; Guo, Yinglu; Xiang, Yong‐Bing; Li, Q Y

doi:10.4238/2014.december.12.19

Cited by 22 publications

(20 citation statements)

References 32 publications

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“…Current evidence supports the idea that both host and tumor RAS are important for tumor growth and angiogenesis in cancer (10,15). As a new part of RAS, the ACE2/Ang-(1-7)/Mas axis also plays an important role in cancer (16,17). Recent studies have shown that low ACE2 expression may be a useful indicator of poor prognosis in HCC and gallbladder cancer (18,19).…”

Section: Discussionmentioning

confidence: 62%

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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Section: Discussionmentioning

confidence: 62%

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

Cheng

Zhou

et al. 2016

Oncology Reports

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“…Most intriguingly, this regulation is diphasic: in the early phase, after 6 h hypoxia, AT1R protein is decreased, whilst AT2R protein is increased; yet if hypoxia is continued up to 24 h this effect is reversed, with AT1R protein significantly increased and AT2R decreased (Fan et al . ). Employing specific pharmacological inhibitors, Fan et al .…”

Section: Discussionmentioning

confidence: 97%

“…Employing specific pharmacological inhibitors, Fan et al . () concluded that this diphasic response may be due to a bi‐directional control mechanism: hypoxia enhances the expression of AT1R and AT2R via increased Ang II, but elevated AT2R inhibits AT1R during the early stage whilst AT1R inhibits AT2R expression as hypoxia continues. This may explain why neither the AT1R nor the AT2R were significantly altered in our hypoxia–reperfusion model.…”

Section: Discussionmentioning

confidence: 99%

“…In other cell systems, such as mouse Lewis lung carcinoma cells, hypoxia appears to upregulate angiotensin-converting enzyme, Ang II, and AT1R. Most intriguingly, this regulation is diphasic: in the early phase, after 6 h hypoxia, AT1R protein is decreased, whilst AT2R protein is increased; yet if hypoxia is continued up to 24 h this effect is reversed, with AT1R protein significantly increased and AT2R decreased (Fan et al 2014). Employing specific pharmacological inhibitors, Fan et al (2014) concluded that this diphasic response may be due to a bi-directional control mechanism: hypoxia enhances the expression of AT1R and AT2R via increased Ang II, but elevated AT2R inhibits AT1R during the early stage whilst AT1R inhibits AT2R expression as hypoxia continues.…”

Section: Figure 2 Gene and Protein Expression Of Placental Ras From mentioning

confidence: 99%

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Human placental renin–angiotensin system in normotensive and pre‐eclamptic pregnancies at high altitude and after acute hypoxia–reoxygenation insult

Kurlak

Mistry

Cindrová‐Davies

et al. 2016

The Journal of Physiology

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Key pointsr The development of the human placenta occurs in a low oxygen environment which stimulates angiogenesis and vascularization.r Placental expression of the renin angiotensin system (RAS) is highest in early pregnancy.Although both the RAS and oxygen stimulate angiogenesis, it is not known how they interact during placental development.r Pre-eclampsia (PE), a condition characterized by poor placental development and elevated oxidative stress has increased incidence in populations living at high altitude and thus exposed to hypobaric hypoxia.r This study aimed to investigate the effects of various forms of oxidative stress on the placental RAS.r The results suggest that the placental RAS is activated by oxidative insults but the component type and the degree of activation is dependent on the nature of the insult.Abstract A functioning placental renin-angiotensin system (RAS) appears necessary for uncomplicated pregnancy and is present during placentation, which occurs under low oxygen tensions. Placental RAS is increased in pre-eclampsia (PE), characterised by placental dysfunction and elevated oxidative stress. We investigated the effect of high altitude hypoxia on the RAS and hypoxia-inducible factors (HIFs) by measuring mRNA and protein expression in term placentae from normotensive (NT) and PE women who delivered at sea level or above 3100 m, using an explant model of hypoxia-reoxygenation to assess the impact of acute oxidative stress on the RAS and HIFs. Protein levels of prorenin (P = 0.049), prorenin receptor (PRR; P = 0.0004), and angiotensin type 1 receptor (AT1R, P = 0.006) and type 2 receptor (AT2R, P = 0.002) were all significantly higher in placentae from NT women at altitude, despite mRNA expression being unaffected. However, mRNA expression of all RAS components was significantly lower in PE at altitude than at sea level, yet PRR, angiotensinogen (AGT) and AT1R proteins were all increased. The increase in transcript and protein expression of all the HIFs and NADPH oxidase 4 seen in PE compared to NT at sea level was blunted at high altitude. Experimentally induced oxidative stress stimulated AGT mRNA (P = 0.04) and protein (P = 0.025). AT1R (r = 0.77, P < 0.001) and AT2R (r = 0.81, P < 0.001) mRNA both significantly correlated with HIF-1β, whilst AT2R also correlated with HIF-1α (r = 0.512, P < 0.013). Our observations suggest that the placental RAS is responsive to changes in tissue oxygenation: this could be important in the interplay between reactive oxygen species as cell-signalling molecules for angiogenesis and hence placental development and function.

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“…RAS was demonstrated to be involved in tumor occurrence and development (46–48). For example, AngII was able to promote epithelial-to-mesenchymal transition in intrahepatic cholangiocarcinoma (38), and angiotensin-converting enzyme inhibitor suppresses growth of colorectal cancer cells (49).…”

Section: Discussionmentioning

confidence: 99%

Resveratrol promotes regression of renal carcinoma cells via a renin-angiotensin system suppression-dependent mechanism

et al. 2016

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The aim of the present study was to investigate the effect of resveratrol on renal carcinoma cells and explore possible renin-angiotensin system-associated mechanisms. Subsequent to resveratrol treatment, the cell viability, apoptosis rate, cytotoxicity levels, caspase 3/7 activity and the levels of angiotensin II (AngII), AngII type 1 receptor (AT1R), vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) were evaluated in renal carcinoma cells. The effects of AngII, AT1R, VEGF and COX-2 on resveratrol-induced cell growth inhibition and apoptosis were also examined. The results indicated that resveratrol treatment may suppress growth, induce apoptosis, and decrease AngII, AT1R, VEGF and COX-2 levels in renal carcinoma ACHN and A498 cells. In addition, resveratrol-induced cell growth suppression and apoptosis were reversed when co-culturing with AT1R or VEGF. Thus, resveratrol may suppress renal carcinoma cell proliferation and induce apoptosis via an AT1R/VEGF pathway.

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Hypoxia induces dysregulation of local renin-angiotensin system in mouse Lewis lung carcinoma cells

Cited by 22 publications

References 32 publications

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

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

Human placental renin–angiotensin system in normotensive and pre‐eclamptic pregnancies at high altitude and after acute hypoxia–reoxygenation insult

Resveratrol promotes regression of renal carcinoma cells via a renin-angiotensin system suppression-dependent mechanism

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