bay-11-7082 and Ovarian-Neoplasms

Ovarian cancer is the leading cause of death among gynecological malignancies. Cyclooxygenase 2 is widely expressed in various cancer cells and participates in the occurrence and development of tumors by regulating a variety of downstream signaling pathways. However, the function and molecular mechanisms of cyclooxygenase 2 remain unclear in ovarian cancer. Here, we demonstrated that cyclooxygenase 2 was highly expressed in ovarian cancer and the expression level was highly correlated with ovarian tumor grades. Further, ovarian cancer cells with high expression of cyclooxygenase 2 exhibit enhanced proliferation and invasion abilities. Specifically, cyclooxygenase 2 promoted the release of prostaglandin E2 upregulated the phosphorylation levels of phospho-nuclear factor-kappa B p65. Celecoxib, AH6809, and BAY11-7082 all can inhibit the promoting effect of cyclooxygenase 2 on SKOV3 and OVCAR3 cell proliferation and invasion. Besides, celecoxib inhibited SKOV3 cell growth in the xenograft tumor model. These data suggest that high expression of cyclooxygenase 2 promotes the proliferation and invasion of ovarian cancer cells through the prostaglandin E2/nuclear factor-kappa B signaling pathway. Cyclooxygenase 2 may be a potential therapeutic target for the treatment of ovarian cancer.

Topics: Animals; Antineoplastic Agents; Celecoxib; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Female; Humans; Mice, Nude; Neoplasm Grading; Neoplasm Invasiveness; NF-kappa B; Nitriles; Ovarian Neoplasms; Phosphorylation; Receptors, Prostaglandin E, EP2 Subtype; Signal Transduction; Sulfones; Transplantation, Heterologous; Xanthones

Ampelopsin has displayed anticancer activity in several types of cancers. However, no evidence has been reported for the direct effect of ampelopsin on ovarian cancer cell migration and invasion, and the underling mechanisms have not yet been clearly established. The aim of the present study was to investigate the influence of ampelopsin on the migration and invasion of ovarian cancer. Proliferation and viability of the ovarian cancer cells were detected by MTT assay. Migration and invasion of the cells were detected, respectively, by scratch wound healing assay and Transwell assay. The expression levels of epithelial-to-mesenchymal transition (EMT) markers were detected at the protein level after stimulation with ampelopsin. Then, the expression levels of NF-κB and p-IκBα were detected with western blot analysis. Meanwhile, an inhibitor of NF-κB was used to investigate the effect of ampelopsin. Finally, the expression of Snail was also detected. Proliferation, migration and invasion of the A2780 cells were all inhibited following the application of ampelopsin. Ampelopsin upregulated E-cadherin and downregulated N-cadherin and vimentin in a concentration- and time-dependent manner. Ampelopsin also exerted its ability to suppress the nuclear translocation of the NF-κB pathway. Administration of the inhibitor BAY11-7082 confirmed the roles of NF-κB in the expression of EMT markers and its transcription factor. These results demonstrated that ampelopsin inhibited EMT and reduced the invasion of ovarian cancer cells via the NF-κB/Snail pathway.

Topics: Active Transport, Cell Nucleus; Antineoplastic Agents; Cadherins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Down-Regulation; Epithelial-Mesenchymal Transition; Female; Flavonoids; Humans; I-kappa B Proteins; Neoplasm Metastasis; NF-kappa B; NF-KappaB Inhibitor alpha; Nitriles; Ovarian Neoplasms; Sulfones; Time Factors; Up-Regulation; Vimentin

Lysophosphatidic acid (LPA) is a biolipid that has diverse biological activities implicated in ovarian cancer initiation and progression. Previous studies have shown the critical role of the Rho/Rho-associated kinase (ROCK) pathway in LPA-induced ovarian cancer progression. However, detailed underlying mechanism by which the Rho/ROCK pathway induces ovarian cancer cell invasion is still incompletely understood. In the present study, we observed that the Rho/ROCK pathway is implicated in the production of proteolytic enzymes, leading to LPA-induced ovarian cancer cell invasion. LPA induced matrix metalloproteinase (MMP)-9 expression in CAOV-3 and PA-1 cells and urokinase-type plasminogen activator (uPA) expression in SKOV-3 cells. LPA-induced proteolytic enzyme expression was required for the invasion of ovarian cancer cells expressing corresponding enzymes. Pretreatment of cells with a pharmacological inhibitor of Rho/ROCK (Y-27632) or overexpression of a dominant-negative mutant of Rho (Rho N19) profoundly inhibited LPA-induced proteolytic enzyme expression as well as the invasive potential of ovarian cancer cells. In addition, transfection with dominant-negative Ras (Ras N17) significantly inhibited LPA-induced Rho activation as well as MMP-9 and uPA expression. Consistently, Y-27632 reduced LPA-induced nuclear factor (NF)-κB activation that is critical for proteolytic enzyme expression and cellular invasion. Collectively, we demonstrate a mechanism by which LPA promotes ovarian cancer progression through coordinate activation of a Ras/Rho/ROCK/NF-κB signaling pathway and the proteolytic enzyme secretion, providing novel biomarkers and promising therapeutic targets for ovarian cancer cell progression.

Topics: Amides; Cell Line, Tumor; Enzyme Inhibitors; Female; Gene Expression Regulation, Neoplastic; Humans; Lysophospholipids; Neoplasm Invasiveness; NF-kappa B; Nitriles; Ovarian Neoplasms; Peptide Hydrolases; Pyridines; rho-Associated Kinases; Sulfones; Urokinase-Type Plasminogen Activator

The development of chemoresistance is a major obstacle for successful anticancer therapy. Understanding the molecular mechanisms leading to chemoresistance is a rational step to improve the therapeutic efficacy of cytotoxic drugs. Since anthracyclines play an important role in cancer chemotherapy, we have generated a human ovarian tumor cell line resistant to sabarubicin (MEN 10755), the newest anthracycline molecule in clinical development. Expression of the transporter protein MRP that affected sabarubicin uptake, and a reduced DNA topoisomerase II content in A2780/saba cells was observed. Since the poisoning of DNA topoisomerase II results in DNA damage, which is a critical signal for NF-kappaB activation, we explored if this transcription factor has a role in the chemoresistance to anthracyclines. We showed a reduced NF-kappaB activation in the resistant cell line. Moreover, qualitative changes in NF-kappaB dimer formation between the two cell lines were observed. In agreement with the hypothesis of a role of NF-kappaB in mediating drug resistance, we showed that the pharmacological inhibition of NF-kappaB activation attenuated drug resistance in A2780/saba cells whereas it had no effect in A2780 cells. Altogether, these findings show that anthracycline resistance in A2780 cell lines is due to the coexpression of several molecular mechanisms.

Topics: Anthracyclines; Antineoplastic Agents, Phytogenic; Blotting, Western; Cell Line, Tumor; Cell Survival; Disaccharides; DNA Topoisomerases, Type I; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Neoplasm; Enzyme Activation; Etoposide; Female; Gene Expression; Humans; Multidrug Resistance-Associated Proteins; NF-kappa B; Nitriles; Ovarian Neoplasms; RNA, Messenger; Signal Transduction; Sulfones; Time Factors; Vinblastine