9-deoxy-delta-9-prostaglandin-d2 and Neoplasms

Prostaglandins (PGs), important modulators in bone biology, may also contribute to tumor formation and progression in human osteosarcoma. 15-Deoxy-Δ(12,14)-PGJ(2) (15d-PGJ(2)), a metabolite of PGD(2) and PPARγ-ligand, exerts a panel of biological activities via receptor-dependent and -independent mechanisms. As inducible cyclooxygenase-2 (Cox-2) is a candidate inflammatory marker in human osteosarcoma and a rate-limiting enzyme in PG biosynthesis, this study aimed at investigating intracellular redox status and signaling cascades leading to Cox-2 induction in human MG-63 osteosarcoma cells. 15d-PGJ(2) induced the accumulation of reactive oxygen species (ROS) that in turn may lead to upregulation of Cox-2 via two different routes in a PPARγ-independent manner. First, phosphorylation of p38 MAPK directly enhances Cox-2 expression by promoting mRNA stability. Second, 15d-PGJ(2) induces activation of epidermal growth factor receptors and downstream activation of Cox-2 via phosphorylation of p42/44 MAPK. Glutathione precursor molecules reversed enhanced ROS levels and Cox-2 expression. Functional activity of Cox-2 expression was tested by measurement of PGE(2) and PGF(2α). The synthetic compound 9,10-dihydro-15d-PGJ(2) lacking the α,β-unsaturated carbonyl group in the cyclopentenone ring did not exhibit the cellular responses observed with 15d-PGJ(2). We conclude that the electrophilic carbon atom of 15d-PGJ(2) is responsible for alterations in intracellular redox status and Cox-2 expression.

Topics: Animals; Cell Line, Tumor; Cyclooxygenase 2; Dinoprost; Dinoprostone; ErbB Receptors; Gene Expression; Glutathione; Humans; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neoplasms; Osteosarcoma; Oxidation-Reduction; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Prostaglandin D2; Reactive Oxygen Species; RNA Stability; Signal Transduction; Up-Regulation

Excessive and prolonged activation of nuclear factor-kappaB (NF-kappaB) has been linked to numerous human diseases, especially cancer, because of the elevated expression of genes encoding antiapoptotic proteins, cytokines, chemokines, cell adhesion molecules, and so on. Eukaryotic cells have developed multiple mechanisms to keep this ubiquitous transcription factor in check. In addition to the inhibitor of kappaB family proteins, a number of endogenous molecules that negatively regulate the activation or activity of NF-kappaB have been identified. These molecules include A20, CYLD, cyPG15-deoxy-Delta(12,14)-prostaglandin J(2), Foxj1, Twist proteins, and beta-arrestins. The extended list of these endogenous inhibitors of NF-kappaB may provide new opportunities for the development of novel strategies for the intervention of malignant transformation. The question to be asked is how NF-kappaB is sustained activated in a number of cancers in which so many antagonists are surrounded.

Topics: Arrestins; beta-Arrestins; Deubiquitinating Enzyme CYLD; DNA-Binding Proteins; Humans; Intracellular Signaling Peptides and Proteins; Neoplasms; NF-kappa B; Nuclear Proteins; Prostaglandin D2; Proteins; Tumor Necrosis Factor alpha-Induced Protein 3; Tumor Suppressor Proteins

Topics: Cell Division; G1 Phase; Gene Expression Regulation, Neoplastic; Genes, myc; Heat-Shock Proteins; Humans; Neoplasms; Prostaglandin D2

Prostaglandin(PG)s of the A and J series are categorized as antitumor, antiviral PGs. They have a reactive alpha, beta-unsaturated carbonyl in the cyclopentenone ring, which could be the active moiety. They are actively incorporated into cells and in part transferred to the nuclei, and lead to cell cycle arrest at G1 or cell death depending on the dose.

Topics: Animals; Antineoplastic Agents; Antiviral Agents; Cell Cycle; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms; Prostaglandin D2; Prostaglandins A; Transplantation, Heterologous; Viruses

Some PG derivatives have been shown to be inhibitory for tumor cell growth. To elucidate the underlying mechanism(s) for this, we examined various DNA polymerase activities in PG-treated cultured cells. Human KBIII cells were exposed for one day to each of PGJ2, delta 7-PGA1 and delta 12-PGJ2 at a concentration of 5 micrograms/ml. The cells were harvested and homogenized, and the cell-free extracts were analyzed by phosphocellulose column chromatography for separation, identification, and quantification of each of the DNA polymerases. The results obtained were as follows: The activity of DNA polymerase alpha, which is responsible for DNA replication, has remained almost unchanged by any of the PG derivatives tested (77-87%), whereas the activity of DNA polymerase beta (repair enzyme) was found to dramatically decrease to 13 to 20% of that of the nontreated control cells by treatment with any of these PG derivatives. The results indicate that (a) these PG derivatives inhibit, either directly or indirectly, the synthesis of DNA polymerase beta in the KBIII cell, and (b) DNA polymerase beta may also participate in DNA replication other than DNA repair.

Topics: Antineoplastic Agents; Cell Division; Cell Line; Humans; Neoplasms; Nucleic Acid Synthesis Inhibitors; Prostaglandin D2; Prostaglandins A, Synthetic; Prostaglandins D; Prostaglandins, Synthetic