Serotonin activates angiogenic phosphorylation signaling in human endothelial cells

Zamani, Ali; Qu, Zhican

doi:10.1016/j.febslet.2012.05.047

Cited by 75 publications

(67 citation statements)

References 28 publications

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“…In human endothelial cells, 5-HT has been shown to activate angiogenic phosphorylation signaling. [40] Neither 5-HT or sertraline increased CD31, an angiogenic marker, or caspase 3, apoptotic marker, in our study. Both 5-HT and sertraline demonstrate mitogenic effects on ovarian neoplastic cells through similar cellular signaling pathways.…”

Section: Discussioncontrasting

confidence: 69%

SSRI use and clinical outcomes in epithelial ovarian cancer

et al. 2016

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Selective serotonin reuptake inhibitor (SSRI) use is common among ovarian cancer patients. We examined the effect of SSRIs on survival and progression in ovarian cancer patients and effects of 5-HT on ovarian cancer cell (OCC) proliferation. Ovarian cancer patients from a 6-site study between 1994 and 2010 were included. Cox proportional hazards models were used for multivariate analysis. SSRI use was associated with decreased time to disease recurrence (HR 1.3, CI 1.0-1.6, p=0.03), but not overall survival (HR 1.1, CI 0.9-1.3, p=0.56). Compared to normal ovarian cells, most OCCs had elevated 5-HT2A receptor mRNA expression (up to 1600 fold greater expression). Clonogenic survival increased in cells treated with 10 uM (1.6 fold, p<0.001) and 20uM (1.9 fold, p=0.018) 5-HT. Mice receiving 5-HT injections had increases in tumor weight (p=0.07) and nodules (p=0.08) with increased Ki67 expression. Injections with sertraline doubled mean tumor weight in mice (p=0.16). 5-HT and sertraline both increased Ki67 expression in mouse tumors (p < 0.001).Patients using SSRIs had significantly decreased time to disease progression. It is possible that SSRIs alter serotonin levels in the tumor microenvironment, resulting in activation of proliferation pathways. Further characterization of serotonergic pathways in ovarian cancer is recommended to demonstrate safety of these medications.

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Section: Discussioncontrasting

confidence: 69%

SSRI use and clinical outcomes in epithelial ovarian cancer

et al. 2016

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“…Previous studies have suggested potential overlap between the 5-HT and VEGF signaling pathways [29], both of which apparently promote cancer cell growth and survival. To determine whether there indeed is overlap between these signaling pathways, we examined whether VEGF expression is altered by 5-HT or inhibitors of signaling pathways involved in the effects of 5-HT.…”

Section: Resultsmentioning

confidence: 99%

“…Although the mechanisms responsible for the effects of 5-HT on the malignant phenotype of breast cancer remain unclear, the angiogenesis-promoting effect of 5-HT suggests that it may stimulate cancer cell proliferation and invasion, the required processes of cancer progression [26–28]. In addition, the signaling pathway associated with angiogenic action of 5-HT is known to be mediated by a mechanism similar to that associated with the angiogenic effect of vascular endothelial growth factor (VEGF) (e.g., via the activation of PI3K/Akt signaling) [29], which suggests potential overlap between signaling molecules with respect to cancer proliferation/invasion and angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Tryptophan hydroxylase 1 and 5-HT7 receptor preferentially expressed in triple-negative breast cancer promote cancer progression through autocrine serotonin signaling

et al. 2016

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BackgroundTriple-negative breast cancer (TNBC) has a high risk of relapse and there are few chemotherapy options. Although 5-hydroxytryptamine (5-HT, serotonin) signaling pathways have been suggested as potential targets for anti-cancer drug development, the mechanism responsible for the action of 5-HT in TNBC remains unknown.MethodsQuantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to measure mRNA and protein levels, respectively. Cell proliferation was measured using CellTiter 96 Aqueous One Solution. siRNA transfection was used to assess involvement of genes in cancer invasion, which were identified by Matrigel transwell invasion assay. Levels of 5-HT and vascular endothelial growth factor (VEGF) were measured using ELISA kits. Chick chorioallantoic membrane (CAM) assay and mouse tumor model were used to investigate the in vivo effects of SB269970, a 5-HT7 receptor antagonist, and BJ-1113, a novel synthetic compound.ResultsTNBC cell lines (MDA-MB-231, HCC-1395, and Hs578T) expressed higher levels of tryptophan hydroxylase 1 (TPH1) than hormone-responsive breast cancer cell lines (MCF-7 and T47D). In MDA-MB-231 cells, 5-HT promoted invasion and proliferation via 5-HT7 receptor, and interestingly, the stimulatory effect of 5-HT on MDA-MB-231 cell invasion was stronger than its effect on proliferation. Likewise, downstream signaling pathways of 5-HT7 differed during invasion and proliferation, that is, Gα-activated cAMP and Gβγ-activated kinase signaling during invasion, and Gβγ-activated PI3K/Akt signaling during proliferation. Also, 5-HT increased the protein expressions of TPH1 and VEGF in MDA-MB-231 cells. These results provide insight of the stimulatory effect of 5-HT on breast cancer progression; 5-HT was found to act more strongly during the first stage of metastasis (during invasion and migration) than during the later proliferative phase after local invasion. Interestingly, these actions of 5-HT were inhibited by BJ-1113, a 6-amino-2,4,5-trimethylpyridin-3-ol analog. BJ-1113 blocked intracellular signaling pathways initiated by 5-HT7 receptor activation, and exhibited anti-proliferative and anti-invasive activities against MDA-MB-231 cells. Furthermore, the inhibitory effect of BJ-1113 against MDA-MB-231 tumor growth was greater than that of SB269970, a 5-HT7 receptor antagonist.Conclusions5-HT7 receptor which mediates 5-HT-induced cancer progression is a potential therapeutic target in TNBC, and BJ-1113 offers a novel scaffold for the development of anti-cancer agents against TNBC.

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“…The opposite effect on iNOS and COX-2 expression is also observed when VSMCs are treated with angiotensin II 16,17) and sphingosine 1-phosphate. 15,18) …”

Section: Function and Signaling Mechanisms In Vascular Smooth Muscle mentioning

confidence: 99%

5-Hydroxytryptamine and Its Receptors in Systemic Vascular Walls

Machida

Iizuka

Hirafuji

2013

Biological & Pharmaceutical Bulletin

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5-hydroxytryptamine (5-HT) in the bloodstream is largely contained in platelets and circulates throughout the entire vascular system. 5-HT released from activated platelets dramatically changes the function of vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). In VSMCs, 5-HT induces proliferation and migration via 5-HT2A receptors. These effects are further enhanced by vasoactive substances such as thromboxane A2 and angiotensin II. 5-HT2A receptor activation in VSMCs also causes both enhancement of prostaglandin I2 production by inducing cyclooxygenase-2 and reduction of nitric oxide (NO) by suppressing inducible NO synthase. Evidence showing that 5-HT in ECs plays a principal role in angiogenesis now exists. Stimulation of 5-HT1 and/or 5-HT2 receptors has been implicated in the angiogenic effect of 5-HT. The extracellular signal-regulated kinase and endothelial NO synthase (eNOS) activation-dependent pathways are involved in the mechanisms. Moreover, 5-HT4 receptors in ECs have been shown to also regulate angiogenesis. Recent reports show sarpogrelate, a selective antagonist of the 5-HT2A receptor, indirectly enhances the function of 5-HT1B receptors in ECs via inhibition of 5-HT2A receptors in VSMCs or platelets. This indirect action of 5-HT1B receptors in ECs may increase NO production derived from eNOS and a vasodilator response. Furthermore, sarpogrelate and other 5-HT2A receptor antagonists have been shown to reduce the constitutive activity of 5-HT2A receptors. It is believed that increasing evidence on the role of 5-HT receptors will contribute to the expansion of the clinical application of existing therapeutic drugs such as sarpogrelate, and to the development of new 5-HT receptor-related drugs for treating cardiovascular diseases.

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Serotonin activates angiogenic phosphorylation signaling in human endothelial cells

Cited by 75 publications

References 28 publications

SSRI use and clinical outcomes in epithelial ovarian cancer

SSRI use and clinical outcomes in epithelial ovarian cancer

Tryptophan hydroxylase 1 and 5-HT7 receptor preferentially expressed in triple-negative breast cancer promote cancer progression through autocrine serotonin signaling

5-Hydroxytryptamine and Its Receptors in Systemic Vascular Walls

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