Bcl-xL/Bax ratio is altered by IFNγ in TNFα- but not in TRAIL-induced apoptosis in colon cancer cell line

Apoptosis is a crucial mechanism to eliminate harmful cells in which growth factors and cytokines are key regulators. In HT29-D4 cells, a model of human colon carcinoma, IFN gamma presensitization is essential to induce an apoptotic response to TNF alpha whereas it only slightly enhances TRAIL-induced apoptosis. To compare the transcriptional profiles induced by TNF alpha and TRAIL and their regulation by IFN gamma, we optimized a cDNA array analysis on targeted signaling pathways and confirmed the gene expression modulations by comparative RT-PCR. Although the two TNFSF ligands induced a same strong up-expression of pro-apoptotic Bax gene, the expression of anti-apoptotic Bcl-xL gene was more strongly up-regulated in TNF alpha- than in TRAIL-stimulated cells. Thus, TRAIL but not TNF alpha induced apoptotic mitochondrial cascade as highlighted by cytochrome c release into cytosol. IFN gamma presensitization of TRAIL-stimulated cells did not induce any change in cytochrome c release, suggesting that the increase of IFN gamma/TRAIL-induced apoptosis is independent of this pathway. In contrast, IFN gamma pretreatment prevented Bcl-xL gene up-expression in TNF alpha-stimulated cells and allowed cytochrome c release. Thus, we hypothesize that the Bcl-xL/Bax ratio can block the apoptotic response in TNF alpha-stimulated cells but allows cell death initiation when it is altered by a crosstalk between IFN gamma presensitization and TNFa induced signalings. (c) 2005 Elsevier B.V. All rights reserved.