oxytocin and Endometrial-Neoplasms

Traditionally, oxytocin (OT) is well known to play a crucial role in the regulation of cyclic changes in the uterus, implantation of the embryo, and parturition. Recently, an additional role for OT has been identified in several types of cancer cells in which OT acts as a growth regulator. In endometrial cancer cells, OT is known to efficiently inhibit cellular proliferation. In the present study, we show that OT increases invasiveness of human endometrial carcinoma (HEC) cells, which are otherwise resistant to the growth-inhibiting effects of OT. Using pharmacological inhibitors, invasion assay, RNA interference, and immunofluorescence, we found that OT enhances the invasive properties of HEC cells through up-regulation of X-linked inhibitor of apoptosis protein (XIAP), matrix-metalloproteinase 2 (MMP2), and matrix-metalloproteinase 14 (MMP14). In addition, we show that OT-mediated invasion is both cyclooxygenase 1 (PTGS1) and cyclooxygenase-2 (PTGS2) dependent via the phosphatidylinositol 3-kinase/AKT (PIK3/AKT) pathway. PTGS2 knockdown by shRNA resulted in XIAP down-regulation. We also show that OT receptor is overexpressed in grade I to III endometrial cancer. Taken together, our results describe for the first time a novel role for OT in endometrial cancer cell invasion.

Topics: Carcinoma; Cell Line, Tumor; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Endometrial Neoplasms; Enzyme Activation; Female; Humans; Isoenzymes; Matrix Metalloproteinase 14; Matrix Metalloproteinase 2; Neoplasm Invasiveness; Oxytocin; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Receptors, Oxytocin; Up-Regulation; X-Linked Inhibitor of Apoptosis Protein

Cell-surface oxytocinase inactivates oxytocin and regulates oxytocin stimulation. We reported that oxytocinase in human endometrial epithelial cells was secreted from the cell membrane in the mid-secretory phase and disappeared from the cell surface. On the other hand, the production in human endometrium of prostaglandins, which play important roles in the reproductive process, has been reported to be upregulated by oxytocin. We investigated whether progesterone affects cell-surface oxytocinase and oxytocin-induced prostaglandin E2 (PGE2) production in vitro. Progesterone induced secretion of oxytocinase into the culture medium, which resulted in a decrease in cell-surface oxytocinase. Production of PGE2 was increased slightly by oxytocin without progesterone, and significantly with progesterone. The inhibition of oxytocinase activity by amastatin had a similar effect to the loss of cell-surface oxytocinase caused by progesterone. It is therefore likely that the cell-surface oxytocinase of endometrial epithelial cells modified by progesterone plays an important role in the function of the human endometrium through PGE2.

Topics: Adenocarcinoma; Adult; Cell Line, Tumor; Cystinyl Aminopeptidase; Dinoprostone; Endometrial Neoplasms; Endometrium; Epithelial Cells; Female; Humans; Membrane Proteins; Oxytocin; Peptides; Progesterone; Protease Inhibitors; Statistics, Nonparametric

Oxytocin (OT) was reported to inhibit the proliferation of various neoplastic tissues and cells, however, the regulation system remains unclear. This study examined the role of OT and its regulatory ability in endometrial adenocarcinoma.. To investigate the possible function of placental leucine aminopeptidase (P-LAP) in endometrial adenocarcinoma, we transfected P-LAP cDNA into A-MEC cells, showing the lowest enzyme activity of P-LAP. Also we examined P-LAP protein expression in human endometrial adenocarcinoma.. We demonstrated the presence of P-LAP, which is identical to cystine aminopeptidase as oxytocinase, in human endometrial adenocarcinoma tissues and found that the expression of P-LAP increase with advances in the grade. Exposure of endometrial adenocarcinoma cell lines to OT caused dose- and time-dependent inhibition of growth. Treatment with 10(-7) M OT for 72 h reduced cell growth by 62, 25, and 30% in A-MEC, HEC1A, and Ishikawa cells, respectively. P-LAP-transfectant cells not only partially recovered from OT-induced growth inhibition but also showed a higher growth rate than parental cells under condition without OT. An OT receptor antagonist and a protein kinase A inhibitor blocked OT-induced growth inhibition in A-MEC and A-MEC-pc cells but not in A-MEC-LAP cells.. These findings suggested that P-LAP might be functionally positive on carcinoma cell growth by degrading suppressive peptides such as OT.

Topics: Adenocarcinoma; Blotting, Western; Cell Division; Cell Line, Tumor; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cystinyl Aminopeptidase; DNA, Complementary; Dose-Response Relationship, Drug; Endometrial Neoplasms; Female; Humans; Immunoblotting; Immunohistochemistry; Oxytocin; Peptides; Plasmids; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Transfection

For a long time, the hypothalamic nonapeptide oxytocin (OT) is known to play a crucial role in many reproductive and behavioral functions. In recent years, a new biological effect of OT has been identified in neoplastic pathology. In this context, OT acts as a growth regulator. through the activation of specific G-coupled transmembrane receptors (OTR). In vitro, an antiproliferative effect of OT was demonstrated in neoplastic cells of either epithelial (mammary and endometrial) or nervous or bone origin, all expressing OTR. Furthermore, the growth-inhibiting effect of OT was also tested and confirmed in mouse and rat mammary carcinomas in vivo. In neoplastic cells from another OT target tissue, trophoblast, the OT effect was to promote proliferation, the opposite of what previously observed in all the other neoplastic OT responsive cells. The signal transduction involved in the OT biological effect was different in OT growth-inhibited or growth-stimulated cells. In the former, the OT effect was mediated by the activation of the cAMP-PKA pathway, a non-conventional OT signaling, whereas in the latter by the increase of intracellular calcium and tyrosine phosphorylation, which are the 'classical' OT transducers. The unexpected role of OT (and OT analogues) in regulating cell proliferation, as well as the diffuse expression of OTR in neoplastic tissue of different origin, open new perspectives on the biological role of the OT-OTR system in cancer.

Topics: Animals; Cell Division; Cyclic AMP-Dependent Protein Kinases; Endometrial Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Mammary Neoplasms, Animal; Mice; Oxytocin; Rats; Receptors, Oxytocin; Signal Transduction; Trophoblasts

Oxytocin receptors (OTRs) are expressed in endometrial cells and oxytocin (OT) participates in endometrial functions. In cancers derived from other OT target tissues, such as breast and neural tissues, the expression of OTRs and the antiproliferative effect of OT on cancer cells has been previously observed. This study was therefore designed to search for OTR expression and the OT effect in endometrial carcinomas. To demonstrate the presence and the location of OTRs and OTR mRNA immunocytochemical, reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ hybridization (ISH) procedures were employed in a series of human adenocarcinomas of the endometrium. Using an anti-OTR monoclonal antibody (IF3), OTRs were demonstrated in the large majority of endometrial carcinomas (82%), with a pattern of positivity varying from diffuse to focal, according to tumour differentiation. The OTR gene was demonstrated in 78% of the cases by RT-PCR and its presence was confirmed in selected cases by ISH. Moreover, in a human endometrial carcinoma cell line (COLO 684) OTR was demonstrated by immunofluorescence and RT-PCR and it was observed that OT treatment (10(-11)-10(-7) M) significantly inhibited cell proliferation. Neither toxic effects nor apoptosis were induced by OT treatment. The addition of an inhibitor of protein kinase A (PKA) to the culture medium abolished the antiproliferative effect of OT, suggesting that cAMP via PKA could be the intracellular mediator of the OT effect, as previously observed in breast and neural tumours. In conclusion, this study presents evidence of OTR expression in human endometrial carcinomas and of an OT antiproliferative effect on human endometrial cancer cells in vitro. It is further suggested that OT and OTR may be involved in the regulation of endometrial cells, not only in physiological conditions but also in a neoplastic context.

Topics: Adenocarcinoma; Apoptosis; Cell Division; Dose-Response Relationship, Drug; Endometrial Neoplasms; Female; Humans; Immunohistochemistry; In Situ Hybridization; Neoplasm Proteins; Oxytocin; Receptors, Oxytocin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured