Ovarian cancer is the most lethal gynecological malignancy due to the silent nature on its early onset and the rapid acquisition of drug resistance. Histologically heterogeneous, it includes several subtypes with different mutational landscapes, hampering the development of effective targeted therapies. Non-coding RNAs are emerging as potential new therapeutic targets in cancer. To search for a microRNA signature related to ovarian carcinomas and study its potential as effective targeted therapy, we examined the expression of 768 miRNA in a large collection of tumor samples and found miR-654-5p to be infraexpressed in ovarian serous carcinomas, the most common and aggressive type. Restoration of miR-654-5p levels reduced tumor cell viability in vitro and in vivo and impaired sphere formation capacity and viability of ovarian cancer patient-derived ascitic cells ex vivo. CDCP1 and PLAGL2 oncogenes were found to be the most relevant direct miR-654-5p targets and both genes convey in a molecular signature associated with key cancer pathways relevant to ovarian tumorigenesis, such as MYC, WNT and AKT pathways. Together, we unveiled the tumor suppressor function of miR-654-5p, suggesting that its restoration or co-targeting of CDCP1 and PLAGL2 may be an effective therapeutic approach for ovarian cancer.

Polo-like kinase 1 (Plk1) is an important mitotic kinase that is crucial for entry into mitosis after recovery from DNA damage-induced cell cycle arrest. Plk1 activation is promoted by the conserved protein Bora (SPAT-1 in C. elegans), which stimulates the phosphorylation of a conserved residue in the activation loop by the Aurora A kinase. In a recent article published in Cell Reports, we show that the master mitotic kinase Cdk1 contributes to Plk1 activation through SPAT-1/Bora phosphorylation. We identified 3 conserved Sp/Tp residues that are located in the N-terminal, most conserved part, of SPAT-1/Bora. Phosphorylation of these sites by Cdk1 is essential for Plk1 function in mitotic entry in C. elegans embryos and during DNA damage checkpoint recovery in mammalian cells. Here, using an untargeted Förster Resonance Energy Transfer (FRET) biosensor to monitor Plk1 activation, we provide additional experimental evidence supporting the importance of these phosphorylation sites for Plk1 activation and subsequent mitotic entry after DNA damage. We also briefly discuss the mechanism of Plk1 activation and the potential role of Bora phosphorylation by Cdk1 in this process. As Plk1 is overexpressed in cancer cells and this correlates with poor prognosis, understanding how Bora contributes to Plk1 activation is paramount for the development of innovative therapeutical approaches.

Identifying novel actionable factors that critically contribute to tumorigenesis is essential in ovarian cancer, an aggressive and disseminative tumor, with limited therapeutic options available. Here we show that Aurora Borealis (BORA), a mitotic protein that plays a key role in activating the master mitotic kinase polo-like kinase 1 (PLK1), has an oncogenic role in ovarian cancer. Gain and loss of function assays on mouse models and ex vivo patient-derived ascites cultures revealed an oncogenic role of BORA in tumor development and a transcriptome-analysis in clinically representative models depicted BORA's role in survival, dissemination and inflammatory cancer related-pathways. Importantly, combinatory treatments of FDA-approved inhibitors against oncogenic downstream effectors of BORA displayed synergistic effect in ovarian cancer models, offering promising therapeutic value. Altogether, our findings uncovered for the first time a critical role of BORA in the viability of human cancer cells providing potential novel therapeutic opportunities for ovarian cancer management.Cancers 2020, 12, 886 2 of 25 in cell cycle division. Nevertheless, even though BORA depletion has been reported to reduce the activity of PLK1 kinase, our understanding of its relevance in cancer is still very limited and there is no comprehensive study that defines the downstream biological consequences of BORA modulation in cancer. Recent evidence has shown that BORA is overexpressed in various tumors such breast, lung, and gastric adenocarcinomas and might serve as a prognostic biomarker [8].Ovarian cancer (OC), the most lethal gynecologic malignancy, is frequently diagnosed at advanced stages with disseminated disease, which limits the therapeutic options [9]. Despite improved cytoreductive surgical approaches and chemotherapy-based regimens, the survival of OC patients has remained largely unchanged during the last two decades [10,11]. Recent advances in cancer genomics have revealed that OC is molecularly a very heterogeneous disease, with extensive genomic instability, copy-number variations and defects in the homologous recombination repair pathway [12]. These genomic aberrations contribute to the development of tumor resistance, hampering effective treatment and ultimately causing disease recurrence [13], but also offer novel potential actionable vulnerabilities that can enhance the effectiveness of existing therapies.Molecular targeted therapies have been implemented routinely into the clinics changing OC management with the inclusion of anti-angiogenic compounds (i.e., monoclonal antibodies such Bevacizumab) [14,15] and poly ADP-ribose polymerases (PARP) inhibitors (i.e., Olaparib or Rucaparib) for breast-cancer (BRCA)-mutated carriers and BRCAness phenotype patients [16,17]. Synthetic lethality produced by PARP inhibitors enhances the therapeutic window after chemotherapy in recurrent platinum-sensitive OC subjects [18]. Nonetheless, it is effective in only a subset of patients, highlighting the urgent clinical need of searching...

No abstract

No abstract

No abstract

Introduction Novel marine compounds supposed an unexplored source of new drugs and expand the possibilities of finding active molecules in all the different signatures of cancer, such as proliferation, invasion and metastases. Here we report the capacity of four marine invertebrate extracts that inhibit proliferation, invasion and migration in colon cancer cell model. Material and methods HCT116 cell line was cultured and exposed to four marine invertebrate extracts (CR from a red coral, PS from an holothurian and NA and NB from nudibranchs) at different concentrations for 24 hour and IC50 was calculated by MTT assay to estimate cytotoxic activity. The rate of cell proliferation and migration was monitored in realtime with the xCELLigence system with E and CIM-16 plates, respectively (Roche Diagnostics GmbH, Germany), which were set in a humidified incubator and maintained in 5% CO2 at 37°C. The impedance value of each well was automatically monitored by the xCELLigence system for 72 hour and expressed as a cell index (CI) value. The anti-invasive rate was determined by Corning BioCoat Matrigel Invasion Chambers with 8.0 mm PET Membrane 24-well Plates (Corning, NY, USA), and crystal violet assay was used to calculate CI. Results and discussions The four marine invertebrate extracts exhibited pronounced cytotoxic and antiproliferative effect in HCT116 model at different doses. The migration assays revealed that CR and especially NB extracts reduced the migration ability of HCT116 cells.Invasion assay let us to isolate superinvasive populations derived from HCT116 which lead to cell models bearing different invasive capabilities (parental (P); invasive subpopulation cells (invaded through membrane four times (I4); and superinvasive line 9 (I9)). Invasive subpopulations I4 and I9 presented a higher rate of invasion than parental population. NB extract showed the best antimigratory capacity compared to other extracts and therefore was selected for further invasive assays. NB showed to reduce invasive cell index in all superinvasive populations. Conclusion The results support the antiproliferative, antimigration and anti-invasive activity of CR, PS, NA and NB marine invertebrate extracts in the highly invasive colon cancer model HCT116. Due to its strong activity, further studies will be focused on the potential of NB extract in the inhibition of metastases-related processes. Introduction Marine invertebrate organisms have received great attention from the scientific community due to its richness in new bioactive compounds with potential anti-proliferative and anticancer activities. In the present study, the cytotoxic efficacy of four marine invertebrate-extracts against human adenocarcinoma colon cancer cells was investigated. Material and methods HT29, SW480 and HGUE-C-1 human colon adenocarcinoma cell lines were cultured and exposed to 4 marine invertebrate extracts at different concentrations for 24 hour. The anti-proliferative properties were examined by MTT assay. Analysis of apoptosis and cell cycle stages wer...

Many eukaryotic genes are cloned in bacterial hosts as fusion polypeptides. Prediction of the secondary structures for some common prokaryotic fusion polypeptides shows that many junction sites correspond to important secondary structures. It is suggested that such structures could affect (hinder, etc.) the conformation or drive the folding of the neighboring eukaryotic counterparts. Thus the prokaryotic junction should be better performed in random coil regions, or short fusion prokaryotic polypeptides should be used.