15-deoxy-delta(12-14)-prostaglandin-j2 and Neoplasms

Peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor, is a ligand-activated transcription factor involved in adipogenesis, glucose homeostasis and lipid metabolism. 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), an endogenous ligand of PPARgamma, has multifaceted cellular functions. Angiogenesis plays an important role in the pathophysiology of ischemic and neoplastic disorders, especially cancer. 15d-PGJ(2) is involved in regulation of angiogenic mediators including vascular endothelial growth factor and hence participates in the blood vessel formation by means of angiogenesis. However, depending on the experimental conditions, this cyclopentenone prostaglandin can exert opposite effects on angiogenesis. 15d-PGJ(2) inhibits angiogenesis via suppression of pro-inflammatory enzymes and cytokines, while it also stimulates angiogenesis via induction of heme oxygenase-1, endothelial nitric-oxide synthase, and hypoxia inducible factor-1alpha. The aim of this review is to highlight such dual effects of 15d-PGJ(2) on angiogenesis and underlying molecular mechanisms.

Topics: Humans; Ligands; Neoplasms; Neovascularization, Pathologic; PPAR gamma; Prostaglandin D2

Chemoprevention refers to the use of defined nontoxic chemical regimens to inhibit, reverse, or retard the process of multistage carcinogenesis that involves multiple signal transduction events. Identification of signaling molecules associated with carcinogenesis as prime targets of chemopreventive agents has become an area of great interest. Recent studies have implicated cysteine thiols present in various transcription factors, such as NF-kappaB, AP-1, and p53 as redox sensors in transcriptional regulation of many genes essential for maintaining cellular homeostasis. Some chemopreventive and cytoprotective agents have been found to target cysteine thiols present in key transcription factors or their regulators, thereby suppressing aberrant over-activation of carcinogenic signal transduction or restoring/normalizing or even potentiating cellular defense signaling. The focus of this review is the oxidation or covalent modification of thiol groups present in key representative redox-sensitive transcription factors and their regulating molecules as a unique strategy for molecular target-based chemoprevention and cytoprotection.

Topics: Cysteine; Humans; Neoplasms; Prostaglandin D2; Signal Transduction; Sulfhydryl Compounds; Transcription Factors; Transcription, Genetic

Prostaglandins are potent lipid molecules that affect key aspects of immunity. The original view of prostaglandins was that they were simply immunoinhibitory. This review focuses on recent findings concerning prostaglandin E2 (PGE2) and the PGD2 metabolite 15-deoxy-Delta(12,14)-PGJ2, and their divergent roles in immune regulation. We will highlight how these two seminal prostaglandins regulate immunity and inflammation, and play an emerging role in cancer progression. Understanding the diverse activities of these prostaglandins is crucial for the development of new therapies aimed at immune modulation.

Topics: Adjuvants, Immunologic; Animals; Dinoprostone; Humans; Inflammation; Models, Immunological; Models, Molecular; Neoplasms; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases

Topics: Apoptosis; Cell Differentiation; Cell Division; Humans; Neoplasms; Prostaglandin D2; Receptors, Cytoplasmic and Nuclear; Transcription Factors

15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), the terminal derivative of the PGJ series, is emerging as a potent antineoplastic agent among cyclopentenone prostaglandins derivatives and also known as the endogenous ligand of peroxisome proliferator-activated receptor gamma (PPARgamma). On the other hand, death receptor 5 (DR5) is a specific receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is one of the most promising candidates for new cancer therapeutics. Here, we report that 15d-PGJ(2) induces DR5 expression at both mRNA and protein levels, resulting in the synergistic sensitization of TRAIL-induced apoptosis in human neoplastic cells, such as Jurkat human leukemia cells or PC3 human prostate cancer cells. 15d-PGJ(2) significantly increased DR5 mRNA stability, whereas it did not activate DR5 promoter activity. Synthetic PPARgamma agonists, such as pioglitazone or rosiglitazone, did not mimic the DR5-inducing effects of 15d-PGJ(2), and a potent PPARgamma inhibitor GW9662 failed to block DR5 induction by 15d-PGJ(2), suggesting PPARgamma-independent mechanisms. Cotreatment with 15d-PGJ(2) and TRAIL enhanced the sequential activation of caspase-8, caspase-10, caspase-9, caspase-3, and Bid. DR5/Fc chimera protein, zVAD-fmk pancaspase inhibitor, and caspase-8 inhibitor efficiently blocked the activation of these apoptotic signal mediators and the induction of apoptotic cell death enhanced by cotreatment with 15d-PGJ(2) and TRAIL. Moreover, a double-stranded small interfering RNA targeting DR5 gene, which suppressed DR5 up-regulation by 15d-PGJ(2), significantly attenuated apoptosis induced by cotreatment with 15d-PGJ(2) and TRAIL. These results suggest that 15d-PGJ(2) is a potent sensitizer of TRAIL-mediated cancer therapeutics through DR5 up-regulation.

Topics: Amino Acid Chloromethyl Ketones; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Caspases; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Enzyme Activation; Gene Expression; Humans; Jurkat Cells; Membrane Glycoproteins; Neoplasms; Pioglitazone; PPAR gamma; Prostaglandin D2; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor; RNA Stability; RNA, Messenger; RNA, Small Interfering; Rosiglitazone; Thiazolidinediones; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha