[Abstract unavailable

The prerequisite of successful implantation depends on achieving the appropriate embryo development to the blastocyst stage and at the same time the development of an endometrium that is receptive to the embryo. Implantation is a very intricate process, which is controlled by a number of complex molecules like hormones, cytokines, and growth factors and their cross talk. A network of these molecules plays a crucial role in preparing receptive endometrium and blastocyst. Furthermore, timely regulation of the expression of embryonic and maternal endometrial growth factors and cytokines plays a major role in determining the fate of embryo. Most of the existing data comes from animal studies due to ethical issues. In this study, we comprehend the data from both animal models and humans for better understanding of implantation and positive outcomes of pregnancy. The purpose of this review is to describe the potential roles of embryonic and uterine factors in implantation process such as prostaglandins, cyclooxygenases, leukemia inhibitory factor, interleukin (IL) 6, IL11, transforming growth factor-b, IGF, activins, NODAL, epidermal growth factor (EGF), and heparin binding-EGF. Understanding the function of these players will help us to address the reasons of implantation failure and infertility.

Background: Loss of keratins 8 and 18 (K8/18) is a hallmark of epithelial-mesenchymal transition (EMT), but its role in tumor progression is unclear. Results: Epithelial cancer cells depleted in K8/18 are more invasive and sensitive to cisplatin through the up-regulation of claudin1. Conclusion: K8/18 loss promotes collective cancer cell migration without inducing EMT. Significance: Cancer cell invasion can arise from K8/18 loss independently of EMT.

The uterus is a primary target for sex steroid action in vivo during the estrous cycle and pregnancy. Cell cultures have been used to determine the specific function of the different cell types forming the uterus. We used endometrial cell cultures previously characterized in our laboratory to study the effect of estradiol (E) and progesterone (P4) on prostaglandin (PG) production and on regulation of the response of the cells to oxytocin (OT). The studies were performed on confluent cultures of epithelial cells grown as a monolayer either on plastic or on filter inserts to allow basal-apical polarization. As described previously, prostaglandin F2 alpha (PGF 2 alpha) production was greater (3.7-fold, p < 0.0001) than prostaglandin E2 (PGE2) production in epithelial cells, and the opposite was true in stromal cells (PGE2 9.9-fold > PGF2 alpha, p < 0.0001). In epithelial cells, the basal production of PGE2 (-61.6%, p < 0.0001) and PGF2 alpha (-51.7%, p < 0.0001) was reduced significantly by E and increased significantly by P4 (PGE2, + 30.0% [p < 0.002]; PGF2 alpha, + 22.2% [p < 0.006]). No significant effect of sex steroids on the basal production of PGs was detected in stromal cells. OT stimulated the production of PGF2 alpha (6.7-fold, p < 0.0001) and PGE2 (9.1-fold, p < 0.0001) in epithelial but not stromal cells. Treatment of the cells with E significantly (p < 0.001) increased OT-stimulated PGF2 alpha production in both the epithelial and stromal cells and that of PGE2 in epithelial cells only. The effect of steroids and OT was similar in polarized (filter) and nonpolarized (plastic) epithelial cells. Analysis of the vectorial secretion of PGs in epithelial cells grown on filter inserts revealed that PGF2 alpha is preferentially secreted in the basal (p < 0.001) compared to the apical compartment. The direction of secretion was not influenced by steroid or OT treatments. The results suggest that epithelial cells of the endometrium are a preferred target for the regulation of PG synthesis by sex steroids and OT.

We located the binding sites of doxorubicin (DOX) and N-(trifluoroacetyl) doxorubicin (FDOX) with bovine serum albumin (BSA) and human serum albumins (HSA) at physiological conditions, using constant protein concentration and various drug contents. FTIR, CD and fluorescence spectroscopic methods as well as molecular modeling were used to analyse drug binding sites, the binding constant and the effect of drug complexation on BSA and HSA stability and conformations. Structural analysis showed that doxorubicin and N-(trifluoroacetyl) doxorubicin bind strongly to BSA and HSA via hydrophilic and hydrophobic contacts with overall binding constants of K DOX-BSA = 7.8 (±0.7)×103 M−1, K FDOX-BSA = 4.8 (±0.5)×103 M−1 and K DOX-HSA = 1.1 (±0.3)×104 M−1, K FDOX-HSA = 8.3 (±0.6)×103 M−1. The number of bound drug molecules per protein is 1.5 (DOX-BSA), 1.3 (FDOX-BSA) 1.5 (DOX-HSA), 0.9 (FDOX-HSA) in these drug-protein complexes. Docking studies showed the participation of several amino acids in drug-protein complexation, which stabilized by H-bonding systems. The order of drug-protein binding is DOX-HSA > FDOX-HSA > DOX-BSA > FDOX>BSA. Drug complexation alters protein conformation by a major reduction of α-helix from 63% (free BSA) to 47–44% (drug-complex) and 57% (free HSA) to 51–40% (drug-complex) inducing a partial protein destabilization. Doxorubicin and its derivative can be transported by BSA and HSA in vitro.

Gynecological cancers are known for being very aggressive at their advanced stages. Indeed, the survival rate of both ovarian and endometrial cancers is very low when diagnosed lately and the success rate of current chemotherapy regimens is not very efficient. One of the main reasons for this low success rate is the acquired chemoresistance of these cancers during their progression. The mechanisms responsible for this acquired chemoresistance are numerous, including efflux pumps, repair mechanisms, survival pathways (PI3K/AKT, MAPK, EGFR, mTOR, estrogen signaling) and tumor suppressors (P53 and Par-4). To overcome these resistances, a new type of therapy has emerged named targeted therapy. The principle of targeted therapy is simple, taking advantage of changes acquired in malignant cancer cells (receptors, proteins, mechanisms) by using compounds specifically targeting these, thus limiting their action on healthy cells. Targeted therapies are emerging and many clinical trials targeting these pathways, frequently involved in chemoresistance, have been tested on gynecological cancers. Despite some targets being less efficient than expected as mono-therapies, the combination of compounds seems to be the promising avenue. For instance, we demonstrate using ChIP-seq analysis that estrogen downregulate tumor suppressor Par-4 in hormone-dependent cells by directly binding to its DNA regulatory elements and inhibiting estrogen signaling could reinstate Par-4 apoptosis-inducing abilities. This review will focus on the chemoresistance mechanisms and the clinical trials of targeted therapies associated with these, specifically for endometrial and ovarian cancers.

Apoptotic cell death plays a normal role in various physiological processes, and deregulated apoptosis is a hallmark of several diseases, including cancer. Cell fate is dictated by the balance between pro-and antiapoptotic factors. Akt is one of these antiapoptotic factors, which must be activated through phosphorylation. The phosphorylation of Akt has previously been shown to be promoted by X-linked inhibitor of apoptosis protein (XIAP), another antiapoptotic protein dictating the fate of normal and cancer cells. However, the underlying mechanisms are poorly understood. We have observed that XIAP associates with PTEN (phosphatase and tensin homolog deleted on chromosome ten), the best characterized negative regulator of Akt phosphorylation, in vitro and in vivo. XIAP knockdown reduces constitutive mono-and polyubiquitination of PTEN, increases PTEN protein levels, and prevents nuclear accumulation of PTEN. Overexpression of XIAP induces polyubiquitination of PTEN and proteasome-dependent decrease of PTEN protein levels. RNA interference experiments showed that XIAP-induced regulation of Akt phosphorylation is PTEN-dependent. Additional experiments confirmed that XIAP also regulates PTEN in vivo; primary mouse embryonic fibroblasts derived from XIAP ؊/؊ mice contain higher levels of PTEN protein, less mono-and polyubiquitinated PTEN, and less nuclear PTEN than primary mouse embryonic fibroblasts derived from XIAP ؉/؉ mice.Finally, we found that XIAP can directly ubiquitinate PTEN in vitro. We thus propose that XIAP acts as an E3 ubiquitin ligase for PTEN and promotes Akt activity by regulating PTEN content and compartmentalization.In normal and cancer cells, balance between survival and apoptosis is maintained by a complex network of proapoptotic and antiapoptotic factors. X-linked inhibitor of apoptosis protein (XIAP) 3 and Akt are two antiapoptotic factors acting on distinct targets. Akt kinase inactivates various proapoptotic factors (1), whereas XIAP binds and sterically inhibits caspases (2). XIAP protein contains a RING domain with E3 ubiquitin ligase activity (3) and has been shown to ubiquitinate caspases to target them for proteasomal degradation (4, 5). XIAP is also thought to promote Akt activity; we have previously reported that overexpression of XIAP promotes Akt phosphorylation in normal and cancerous ovarian cells (6, 7). The mechanisms through which XIAP promotes Akt phosphorylation, however, have not been investigated.Akt phosphorylation is positively regulated by phosphatidylinositol (PI) 3-phosphate kinase, which converts phosphatidylinositol 2-phosphate (PIP2) into PIP3, allowing recruitment and phosphorylation of Akt by PDK1 (8). PIP3-induced Akt phosphorylation, however, is antagonized by PTEN (phosphatase and tensin homolog deleted on chromosome ten), which converts PIP3 into PIP2 (9). PTEN content and activity are regulated transcriptionally (10) and post-translationally (11,12). Similar to several other proteins, polyubiquitination of PTEN leads to proteasome-dependent degradation (12). ...

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