Ligands of the peripheral benzodiazepine receptor induce apoptosis and cell cycle arrest in oesophageal cancer cells: involvement of the p38MAPK signalling pathway

Abstract

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.

Comparative Anticancer Effects of Flavonoids and Diazepam in Cultured Cancer Cells

“…However, PBR as a critical part of the mitochondrial permeability transition pore (mPT) has been shown to mediate enhancing the apoptosis. [9][10][11][12][13][14] In a previous study by the current authors, 21) anticancer cytotoxic flavonoids including apigenin elicited up-regulation of PBR mRNA expression in SK-N-Mc human neuroblastoma cells. Moreover, in this study, treatment with PBR ligands consistently inhibited the SNU-C4 cell survival, and diazepam also produced anticancer cytotoxic effects, similar to those caused by flavonoids.…”

Peripheral benzodiazepine receptor (PBR) ligand cytotoxicity unrelated to PBR expression

“…5D). However in these cells, the has already been questioned in several studies where the concentration range needed to achieve a toxic effect was always two or three orders of magnitude higher than the affinity of PBR ligands for their receptor [8][9][10][11][12]. Furthermore, a similar debate existed about the effect of PBR ligands on cell proliferation [43], and it has just been demonstrated that such a property was independent of their ability to bind PBR [44].…”

Gadd45 Proteins Induce G2/M Arrest and Modulate Apoptosis in Kidney Cells Exposed to Hyperosmotic Stress

“…The present study, viewed in the context of our previously reported data, suggests that the p38 pathway promotes G 2 arrest via Gadd45␣ induction in response to hyperosmolality. Gadd45␣ induction also depends on p38 activity in human neuroblastoma cells exposed to oxidative stress (45), human epithelial cells exposed to flavonoids (46), and esophageal cancer cells exposed to peripheral benzodiazepine receptor-specific ligands (47). Conversely, p38 activity depends on MEKK4 activation mediated by each of the three Gadd45 proteins in response to a diverse array of stimuli (5,26,48,49).…”