Oxytocin inhibits the proliferation of MDA-MB231 human breast-cancer cellsvia cyclic adenosine monophosphate and protein kinase A

Cassoni, Paola; Sapino, Anna; Fortunati, Nicoletta; Munaron, Luca; Chini, Bice; Bussolati, Gianni

doi:10.1002/(sici)1097-0215(19970717)72:2<340::aid-ijc23>3.0.co;2-i

Cited by 84 publications

(69 citation statements)

References 23 publications

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“…Indeed, the antiproliferative effect of OT, mediated by OTR, has been documented in breast cancer cells (28) and other tumors (29,30). In contrast to its action on tumoral cells, a mitogenic action of OT by phosphorylation and activation of mitogen-activated protein kinase has been described in myometrium (31).…”

Section: Discussionmentioning

confidence: 99%

Oxytocin in cardiac ontogeny

Jankowski

Danalache²,

Wang³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

102

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Previous studies demonstrated the presence of oxytocin (OT) and oxytocin receptors (OTRs) in the heart. The present work provides results supporting a potential role of OT in cardiomyogenesis. Here, we show a maximal OT and OTR protein level in the developing rat heart at day 21 of gestation and postnatal days 1-4, when cardiac myocytes are at a stage of intense hyperplasia. Between postnatal days 1 and 66, OT decreased linearly in all heart chambers (4.1-to 6.6-fold). Correspondingly, immunocytochemistry demonstrated that OTRs, which were eminent in postnatal cardiomyocytes, declined with age to low levels in adults. Interestingly, in coronary vasculature, OTRs developed in endothelial cells at postnatal days 12 and 22 and achieved a plateau in adult rats. These findings suggest that OT can be involved in developmental formation of the coronary vessels. In vivo, the OT͞OTR system in the fetal heart was sensitive to the actions of retinoic acid (RA), recognized as a major cardiac morphogen. RA treatment produced a significant increase (2-to 3-fold) both in the OT concentration and in the OT mRNA levels. Ex vivo, an OT antagonist inhibited RA-mediated cardiomyocyte differentiation of P19 embryonic stem cells. The decline of cardiac OT expression from infancy to adulthood of the rat and changes in cell types expressing OTR indicate a dynamic regulation of the OT system in the heart rather than constitutive expression. The results support the hypothesis that RA induces cardiomyogenesis by activation of the cardiac OT system. heart development ͉ oxytocin receptors ͉ retinoic acid ͉ oxytocin antagonist ͉ cardiomyocyte differentiation O xytocin (OT), recognized traditionally as a reproductive hormone with a major role in childbirth and lactation, is produced in high concentrations in the hypothalamic supraoptic nucleus and paraventricular nucleus, then transported from these source nuclei to the posterior pituitary by neurosecretion (1). Longitudinal studies of neural and hormonal circuits activated by experimental volume expansion have identified OT as a major regulator of cardiovascular functions (reviewed in refs. 2 and 3). OT, injected peripherally, causes a decrease of arterial pressure (4) while reducing both heart rate and the force of contractions in isolated atria (5). OT acts via neuroendocrine͞ endocrine͞paracrine pathways to release atrial natriuretic peptide (ANP) from the heart (6, 7). ANP is a potent diuretic, natriuretic, and vasorelaxant hormone that is also involved in cell growth regulation. In addition, we have demonstrated that in isolated, perfused hearts, an OT antagonist (OTA) blocks basal ANP release (7), suggesting the presence of local OT in the heart. Further study revealed cardiac OT synthesis (8), with OT being detected in the medium of cultured neonatal rat cardiomyocytes (9).Recently, we showed that P19 embryonic carcinoma cells, a model of mouse embryonic stem cells, express OT receptors (OTRs), and OT stimulates the differentiation of these cells into beating cell colonies expressing ...

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Section: Discussionmentioning

confidence: 99%

Oxytocin in cardiac ontogeny

Jankowski

Danalache²,

Wang³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

102

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“…The antiproliferative effect of OT, mediated by OT receptors (OTRs), has been documented in breast cancer cells (9) and other tumors (10)(11)(12). In contrast to its effect on tumoral cells, a mitogenic action of OT has also been described.…”

mentioning

confidence: 99%

Oxytocin induces differentiation of P19 embryonic stem cells to cardiomyocytes

Paquin

Danalache

Jankowski

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

210

175

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We recently discovered the existence of the oxytocin͞oxytocin receptor (OT͞OTR) system in the heart. Activation of cardiac OTR stimulates the release of atrial natriuretic peptide (ANP), which is involved in regulation of blood pressure and cell growth. Having observed elevated OT levels in the fetal and newborn heart at a stage of intense cardiomyocyte hyperplasia, we hypothesized a role for OT in cardiomyocyte differentiation. We used mouse P19 embryonic stem cells to substantiate this potential role. P19 cells give rise to the formation of cell derivatives of all germ layers. Treatment of P19 cell aggregates with dimethyl sulfoxide (DMSO) induces differentiation to cardiomyocytes. In this work, P19 cells were allowed to aggregate from day 0 to day 4 in the presence of 0.5% DMSO, 10 ؊7 M OT and͞or 10 ؊7 M OT antagonist (OTA), and then cultured in the absence of these factors until day 14. OT alone stimulated the production of beating cell colonies in all 24 independently growing cultures by day 8 of the differentiation protocol, whereas the same result was obtained in cells induced by DMSO only after 12 days. Cells induced with OT exhibited increased ANP mRNA, had abundant mitochondria (i.e., they strongly absorbed rhodamine 123), and expressed sarcomeric myosin heavy chain and dihydropyridine receptor-␣1, confirming a cardiomyocyte phenotype. In addition, OT as well as DMSO increased OTR protein and OTR mRNA, and OTA completely inhibited the formation of cardiomyocytes in OT-and DMSO-supplemented cultures. These results suggest that the OT͞OTR system plays an important role in cardiogenesis by promoting cardiomyocyte differentiation.

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“…Patients with schizophrenia show a deficit in detecting odors that release low levels of cAMP (e.g., lyral), but their ability to detect compounds associated with high release of cAMP (e.g., citralva) is intact (Turetsky and Moberg, 2009). Interestingly, in vitro work suggests that oxytocin can increase cAMP, suggesting that this may be the mechanism by which it enhances olfactory detection of lyral in patients with schizophrenia (Cassoni et al, 1997). Due to citralva's high cAMP release, we hypothesize that oxytocin would have little effect on patients' detection threshold for citralva (Turetsky and Moberg, 2009).…”

Section: Discussionmentioning

confidence: 99%

Oxytocin administration selectively improves olfactory detection thresholds for lyral in patients with schizophrenia

Woolley

Lam

Chuang

et al. 2015

Psychoneuroendocrinology

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SummaryBackground-Olfaction plays an important role in mammalian social behavior. Olfactory deficits are common in schizophrenia and correlate with negative symptoms and low social drive. Despite their prominence and possible clinical relevance, little is understood about the pathological mechanisms underlying olfactory deficits in schizophrenia and there are currently no effective treatments for these deficits. The prosocial neuropeptide oxytocin may affect the olfactory system when administered intranasally to humans and there is growing interest in its therapeutic potential in schizophrenia.Methods-To examine this model, we administered 40 IU of oxytocin and placebo intranasally to 31 patients with a schizophrenia spectrum illness and 34 age-matched healthy control participants in a randomized, double-blind, placebo-controlled, cross-over study. On each test day, participants completed an olfactory detection threshold test for two different odors: (1) lyral, a synthetic fragrance compound for which patients with schizophrenia have specific olfactory detection threshold deficits, possibly related to decreased cyclic adenosine 3′,5′-monophosphate (cAMP) signaling; and (2) anise, a compound for which olfactory detection thresholds change with menstrual cycle phase in women.Results-On the placebo test day, patients with schizophrenia did not significantly differ from healthy controls in detection of either odor. We found that oxytocin administration significantly and selectively improved olfactory detection thresholds for lyral but not for anise in patients with schizophrenia. In contrast, oxytocin had no effect on detection of either odor in healthy controls. ContributorsJosh Woolley designed the study and supervised all data collection and analysis and manuscript writing. Olivia Lam helped manage various aspects of the study including data collection and recruitment of participants and assisted with manuscript writing. Brandon Chuang assisted with data collection, data management, statistical analyses, and manuscript writing. Judith Ford consulted with the team about data analysis and helped edit the manuscript. Dan H. Mathalon assisted with study design and data analysis. Sophia Vinogradov assisted with study design and data analysis. All authors contributed to and have approved the final manuscript. Conflict of interest statementDan Mathalon is a consultant to Bristol Myers Squibb Inc. Sophia Vinogradov is a consultant to Brain Plasticity Institute. The remaining authors declare that they have no conflicts of interest. U.S. Department of Veterans Affairs VA Author ManuscriptVA Author Manuscript VA Author ManuscriptDiscussion-Our data indicate that oxytocin administration may ameliorate olfactory deficits in schizophrenia and suggest the effects of intranasal oxytocin may extend to influencing the olfactory system. Given that oxytocin has been found to increase cAMP signaling in vitro a possible mechanism for these effects is discussed.

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Oxytocin inhibits the proliferation of MDA-MB231 human breast-cancer cellsvia cyclic adenosine monophosphate and protein kinase A

Cited by 84 publications

References 23 publications

Oxytocin in cardiac ontogeny

Oxytocin in cardiac ontogeny

Oxytocin induces differentiation of P19 embryonic stem cells to cardiomyocytes

Oxytocin administration selectively improves olfactory detection thresholds for lyral in patients with schizophrenia

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