NFAT5/STAT3 interaction mediates synergism of high salt with IL-17 towards induction of VEGF-A expression in breast cancer cells

Amara, Suneetha; Alotaibi, Dalal; Tiriveedhi, Venkataswarup

doi:10.3892/ol.2016.4713

Cited by 39 publications

(41 citation statements)

References 42 publications

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“…Briefly, total RNA was extracted from 10 6 cells using TRIzol reagent (Sigma–Aldrich, St Louis, MO) and analyzed as mentioned previously [7, 20, 21]. RNA samples were quantified by absorbance at 260nm.…”

Section: Methodsmentioning

confidence: 99%

Critical role of SIK3 in mediating high salt and IL-17 synergy leading to breast cancer cell proliferation

et al. 2017

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Chronic inflammation is a well-known precursor for cancer development and proliferation. We have recently demonstrated that high salt (NaCl) synergizes with sub-effective interleukin (IL)-17 to induce breast cancer cell proliferation. However, the exact molecular mechanisms mediating this effect are unclear. In our current study, we adopted a phosphoproteomic-based approach to identify salt modulated kinase-proteome specific molecular targets. The phosphoprotemics based binary comparison between heavy labelled MCF-7 cells treated with high salt (Δ0.05 M NaCl) and light labelled MCF-7 cells cultured under basal conditions demonstrated an enhanced phosphorylation of Serine-493 of SIK3 protein. The mRNA transcript and protein expression analysis of SIK3 in MCF-7 cells demonstrated a synergistic enhancement following co-treatment with high salt and sub-effective IL-17 (0.1 ng/mL), as compared to either treatments alone. A similar increase in SIK3 expression was observed in other breast cancer cell lines, MDA-MB-231, BT20, and AU565, while non-malignant breast epithelial cell line, MCF10A, did not induce SIK3 expression under similar conditions. Biochemical studies revealed mTORC2 acted as upstream mediator of SIK3 phosphorylation. Importantly, cell cycle analysis by flow cytometry demonstrated SIK3 induced G0/G1-phase release mediated cell proliferation, while SIK3 silencing abolished this effect. Also, SIK3 induced pro-inflammatory arginine metabolism, as evidenced by upregulation of the enzymes iNOS and ASS-1, along with downregulation of anti-inflammatory enzymes, arginase-1 and ornithine decarboxylase. Furthermore, gelatin zymography analysis has demonstrated that SIK3 induced expression of tumor metastatic CXCR4 through MMP-9 activation. Taken together, our data suggests a critical role of SIK3 in mediating three important hallmarks of cancer namely, cell proliferation, inflammation and metastasis. These studies provide a mechanistic basis for the future utilization of SIK3 as a key drug discovery target to improve breast cancer therapy.

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Section: Methodsmentioning

confidence: 99%

Critical role of SIK3 in mediating high salt and IL-17 synergy leading to breast cancer cell proliferation

et al. 2017

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“…CDK5, c-Abl, and ATM promote the nuclear localization of NFAT5, and, in contrast, CK1 inhibits its nuclear accumulation [19]. There are many other factors that influence the activation and expression of NFAT5, such as inflammatory cytokines [16, 77], microRNAs [50, 62, 78, 79], and transcription factors [80-83]. …”

Section: The Regulation Of Nfat5 Activationmentioning

confidence: 99%

NFAT5 Has a Job in the Brain

Yang

Wang

Peng³

2018

Dev Neurosci

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Nuclear factor of activated T cells 5 (NFAT5) has recently been classified as a new member of the Rel family. In addition, there are 5 more well-defined members (NF-κB and NFAT1–4) in the Rel family, which participate in regulating the expression of immune and inflammatory response-related genes. NFAT5 was initially identified in renal medullary cells where it regulated the expression of osmoprotective-related genes during the osmotic response. Many studies have demonstrated that NFAT5 is highly expressed in the nuclei of neurons in fetal and adult brains. Additionally, its expression is approximately 10-fold higher in fetal brains. With the development of detection technologies (laser scanning confocal microscopy, transgene technology, etc.), recent studies suggest that NFAT5 is also expressed in glial cells and plays a more diverse functional role. This article aims to summarize the current knowledge regarding the expression of NFAT5, its regulation of activation, and varied biological functions in the brain.

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“…Numerous studies have revealed that the treatment of hypertension, targeted to RAS components (AT1 blockers, ACE inhibitors), is associated with the suppression of VEGF-A-mediated tumor development, better survival and a lower risk of the development of cancer (Yoshiji et al 2002;Dai et al 2015;Fan et al 2016). Moreover, a recent study implied that breast cancer cells increased the expression of VEGF-A after exposure to high NaCl levels compared to control cells (Amara et al 2016). In our experiment, we observed a significant positive correlation between the AT1 receptor and VEGF-A mRNA expression in the liver of the female control group.…”

Section: Discussionmentioning

confidence: 99%

Sex and salt intake dependent renin-angiotensin plasticity in the liver of the rat

Pidíková

Svitok

Herichová

2019

Endocrine Regulations

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Objective. Epidemiological studies confirm that hypertensive patients respond differently to renin-angiotensin system (RAS) inhibition depending on their gender. The aim of present work is to focus on sex-dependent differences in RAS regulation under conditions of increased salt intake.Method. To investigate RAS, we measured the expression of angiotensinogen (Agt) mRNA, angiotensin receptor type 1 (AT1) mRNA and mitochondria assembly receptor (MasR) in the liver of rats under control conditions and after feeding with a salt diet (2% NaCl). In parallel, vascular endothelial growth factor A (VEGF-A) mRNA was analyzed.Results. Regression analysis revealed sex-dependent differences in the correlation between mRNA expression of AT1 and that of Agt, MasR and VEGF-A in both groups. There was a significant negative correlation between AT1 and Agt mRNA expression in the male control group, but this correlation disappeared in males exposed to a salt diet. In females, AT1 and Agt expression correlated only in the group exposed to the salt diet. In control males, there was a borderline trend to correlation between AT1 and MasR mRNA expression. The correlation between AT1 and VEGF-A mRNA expression was significant only in the control females, however, after exposure to a salt diet, this correlation diminished.Conclusions. We hypothesize that RAS components expression is compensated differently in males and females. The observed loss of compensatory relationships in RAS between AT1 and Agt and AT1 and MasR in male rats under a salt diet can contribute to the differences observed in human with hypertension associated with an unhealthy diet.

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NFAT5/STAT3 interaction mediates synergism of high salt with IL-17 towards induction of VEGF-A expression in breast cancer cells

Cited by 39 publications

References 42 publications

Critical role of SIK3 in mediating high salt and IL-17 synergy leading to breast cancer cell proliferation

Critical role of SIK3 in mediating high salt and IL-17 synergy leading to breast cancer cell proliferation

NFAT5 Has a Job in the Brain

Sex and salt intake dependent renin-angiotensin plasticity in the liver of the rat

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