osteoprotegerin and Ovarian-Neoplasms

Genotoxic agents are widely used anti-cancer therapies because of their ability to interfere with highly proliferative cells. An important outcome of these interventions is the induction of a state of permanent arrest also known as cellular senescence. However, senescent cancer cells are characterized by genomic instability and are at risk of escaping the growth arrest to eventually facilitate cancer relapse. The tumor necrosis factor related apoptosis inducing ligand (TRAIL) signals extrinsic apoptosis via Death Receptors (DR) 4 and 5, while Decoy Receptors (DcR) 1 and 2, and Osteoprotegerin (OPG) are homologous to death receptors but incapable of transducing an apoptotic signal. The use of recombinant TRAIL as an anti-cancer strategy in combination with chemotherapy is currently in development, and a major question remains whether senescent cancer cells respond to TRAIL. Here, we show variable sensitivity of cancer cells to TRAIL after senescence induction, and upregulation of both pro-apoptotic and anti-apoptotic receptors in therapy-induced senescent cancer cells. A DR5-selective TRAIL variant (DHER), unable to bind to DcR1 or OPG, was more effective in inducing apoptosis of senescent cancer cells compared to wild-type TRAIL. Importantly, no apoptosis induction was observed in non-cancerous cells, even at the highest concentrations tested. Our results suggest that targeting DR5 can serve as a novel therapeutic strategy for the elimination of therapy-induced senescent cancer cells.

Topics: Apoptosis; Breast Neoplasms; Cellular Senescence; Doxorubicin; Female; Gene Expression Regulation, Neoplastic; Genomic Instability; GPI-Linked Proteins; Humans; MCF-7 Cells; Osteoprotegerin; Ovarian Neoplasms; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor, Member 10c; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor Decoy Receptors

Topics: Apoptosis Inducing Factor; Apoptosis Regulatory Proteins; Biomarkers; Carrier Proteins; Female; Humans; Osteoprotegerin; Ovarian Neoplasms; RANK Ligand

Protein and antibody arrays have emerged as a promising technology to study protein expression and protein function in a high-throughput manner. These arrays also represent a new opportunity to profile protein expression levels in cancer patients' samples and to identify useful biosignatures for clinical diagnosis, disease classification, prediction, drug development and patient care. We applied antibody arrays to discover a panel of proteins which may serve as biomarkers to distinguish between patients with ovarian cancer and normal controls.. Using a case-control study design of 34 ovarian cancer patients and 53 age-matched healthy controls, we profiled the expression levels of 174 proteins using antibody array technology and determined the CA125 level using ELISA. The expression levels of those proteins were analyzed using 3 discriminant methods, including artificial neural network, classification tree and split-point score analysis. A panel of 5 serum protein markers (MSP-alpha, TIMP-4, PDGF-R alpha, and OPG and CA125) was identified, which could effectively detect ovarian cancer with high specificity (95%) and high sensitivity (100%), with AUC =0.98, while CA125 alone had an AUC of 0.87.. Our pilot study has shown the promising set of 5 serum markers for ovarian cancer detection.

Topics: Adult; Aged; Antibodies; Biomarkers, Tumor; CA-125 Antigen; Case-Control Studies; Cluster Analysis; Enzyme-Linked Immunosorbent Assay; Female; Humans; Microarray Analysis; Middle Aged; Neural Networks, Computer; Osteoprotegerin; Ovarian Neoplasms; Proteomics; Receptor, Platelet-Derived Growth Factor alpha; Reproducibility of Results; Sensitivity and Specificity; Tissue Inhibitor of Metalloproteinase-4; Tissue Inhibitor of Metalloproteinases

TRAIL, tumor necrosis factor-related apoptosis-inducing ligand, is a recently identified cytokine that preferentially kills transformed cells while sparing most normal cells.. We investigated the ability of TRAIL alone and TRAIL in combination with cytotoxic drugs to induce apoptosis in six ovarian cancer cell lines. To get some insight into the resistance to TRAIL, the expression of TRAIL receptors and selected downstream signaling elements was determined.. TRAIL induced significant apoptosis (up to 80%) in three out of six ovarian cancer cell lines (MZ-26, CaOV-3, ES-2). In A2780 and A2780ADR cells, resistance to TRAIL-induced apoptosis correlated with their lack of DR4-expression. MZ-15 cells, which expressed the processed form of FLIP(L), p43 (FADD-like IL-1beta-converting enzyme (FLICE)-like inhibitory protein (FLIP)), and FLIP(S), were resistant to TRAIL in spite of the presence of DR4. When TRAIL-resistant cell lines were co-incubated with routinely used cytotoxic agents, TRAIL exerted a synergistic effect leading to apoptosis rates unachievable by incubation with cytotoxic agents alone.. The ability of TRAIL to induce apoptosis in ovarian cancer cells as well as to potentiate the activity of chemotherapeutic agents even in cell lines that are resistant to TRAIL-induced cytotoxicity is a powerful promise in the fight against this deadly disease.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Carboplatin; Carrier Proteins; CASP8 and FADD-Like Apoptosis Regulating Protein; Caspase 8; Caspases; Cell Line, Tumor; Chondrocytes; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Neoplasm; Drug Synergism; Endothelium, Vascular; Female; Gene Expression Regulation, Neoplastic; Glycoproteins; Humans; Intracellular Signaling Peptides and Proteins; Membrane Glycoproteins; Osteoprotegerin; Ovarian Neoplasms; Paclitaxel; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Recombinant Proteins; TNF-Related Apoptosis-Inducing Ligand; Topotecan; Tumor Necrosis Factor-alpha