ro-41-5253 and Lung-Neoplasms

Proinflammatory cytokines, lipopolysaccharide (LPS), and neutrophil elastase (NE) have been implicated in the induction of hypersecretion of respiratory mucus. In this study, we demonstrated that interleukin-1beta (IL-1beta) increased MUC2 and MUC5AC mRNA levels 2- to 3-fold in a time- and dose-dependent manner in NCI-H292 cells. In contrast, MUC5B mRNA was not significantly changed. A transcription inhibitor blocked the stimulation of MUC2 and MUC5AC gene expression by IL-1beta. A translation inhibitor did not interfere with the induction of MUC2 mRNA expression, whereas stimulation of MUC5AC mRNA was blocked, suggesting de novo protein synthesis is required for the stimulation of MUC5AC mRNA. We previously reported that induction of MUC2, MUC5AC, and MUC5B gene expressions by retinoic acid is mediated by the retinoic acid receptor (RARalpha), and inhibited by the specific RARalpha antagonist Ro 41-5253. Here, we demonstrate that the RARalpha antagonist can effectively inhibit IL-1beta-induced MUC2 and MUC5AC gene expression and reduce intracellular MUC5AC protein. Further investigation showed that the RARalpha antagonist also inhibited the stimulation of MUC2 and MUC5AC mRNA expression by tumor necrosis factor-alpha, LPS, and NE.

Topics: Benzoates; Chromans; Gene Expression Regulation, Neoplastic; Humans; Interleukin-1; Leukocyte Elastase; Lipopolysaccharides; Lung Neoplasms; Mucin 5AC; Mucin-2; Mucins; Neoplasm Proteins; Protein Biosynthesis; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoids; RNA Stability; RNA, Messenger; Transcription, Genetic; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

In this study, we show that all-trans-retinoic acid (RA) is a potent inducer of tissue transglutaminase (TGase II) and apoptosis in the rat tracheobronchial epithelial cell line SPOC-1. We demonstrate that these cells express the retinoid receptors RAR alpha, RAR gamma, and RXR beta. To identify which of these receptors are involved in regulating these processes, we analyzed the effects of several receptor-selective agonists, an antagonist, and a dominant-negative RAR alpha. We show that the RAR-selective retinoid SRI-6751-84 strongly increased TGase II expression at both the protein and mRNA levels, whereas the RXR-selective retinoid SR11217 had little effect. The RAR alpha-selective retinoid Ro40-6055 was also able to induce TGase II, whereas the RAR gamma-selective retinoid CD437 was inactive. The induction of TGase II by the RAR-selective retinoid was completely inhibited by the RAR alpha-antagonist Ro41-5253. Overexpression of a truncated RAR alpha gene with dominant-negative activity also inhibited the induction of TGase II expression. The increase in TGase II is associated with an induction of apoptosis as revealed by DNA fragmentation and the generation of apoptotic cells. We demonstrate that apoptosis is affected by retinoids in a manner similar to TGase II. Our results suggest that the induction of TGase II expression and apoptosis in SPOC-1 cells are mediated through an RAR alpha-dependent signaling pathway.

Topics: Animals; Apoptosis; Benzoates; Bronchi; Cell Line; Cell Nucleus; Chloramphenicol O-Acetyltransferase; Chromans; Chromatin; Enzyme Induction; Epithelium; Gene Expression; Humans; Luciferases; Lung Neoplasms; Rats; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Retinoic Acid Receptor gamma; Retinoid X Receptors; Retinoids; Signal Transduction; Tetrahydronaphthalenes; Trachea; Transcription Factors; Transfection; Transglutaminases; Tumor Cells, Cultured