Ligands of the peripheral benzodiazepine receptor induce apoptosis and cell cycle arrest in oesophageal cancer cells: involvement of the p38MAPK signalling pathway.
Specific ligands of the peripheral benzodiazepine receptor (PBR) are known to induce apoptosis and cell cycle arrest in oesophageal cancer cells. However, the underlying mechanisms are still unknown. Here, we investigated the transcriptional alterations and activation of protein kinases in response to PBR-specific ligands. Using cDNA arrays, we examined the transcriptional effects of the PBR-specific ligand FGIN-1-27 in two oesophageal cancer cell lines, KYSE-140 (squamous cell carcinoma) and OE-33 (adenocarcinoma). In oesophageal cancer cells, FGIN-1-27 induced extensive changes in the expression of genes involved in the regulation of apoptosis and cell cycle. Both in oesophageal cancer cell lines (KYSE-140, OE-33) we observed a strong upregulation of the growth arrest and DNA-damage-inducible genes, gadd45 and gadd153, in response to PBR ligands. gadd genes are known to be induced by p38MAPK activation. Using Western blotting we detected a time- and dose-dependent phosphorylation of p38MAPK, which was found to be functionally involved in gadd induction, apoptosis, and cell cycle arrest. In conclusion, our data indicate that PBR-specific ligands cause apoptosis and cell cycle arrest by activation of the p38MAPK pathway and induction of gadd45 and gadd153.
Sutter
A P
AP
Medical Clinic I, Gastroenterology, Infectious Diseases, Rheumatology, University Hospital Benjamin Franklin, Free University of Berlin, Hindenburgdamm 30, 12200 Berlin, Germany.
Maaser
K
K
Barthel
B
B
Scherübl
H
H
D017209:Apoptosis; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology*; D002453:Cell Cycle; D004249:DNA Damage; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007210:Indoleacetic Acids / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011506:Proteins; D011963:Receptors, GABA-A / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases; D000097642:GADD45 Proteins
D022762:CCAAT-Enhancer-Binding Proteins; D007210:Indoleacetic Acids; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases; D011506:Proteins; D011963:Receptors, GABA-A; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; D000097642:GADD45 Proteins; C497249:DDIT3 protein, human; C081306:N,N-di-n-hexyl-2-(4-fluorophenyl)indole-3-acetamide