LPS promotes resistance to TRAIL-induced apoptosis in pancreatic cancer.

BACKGROUND: Though TRAIL has been hailed as a promising drug for tumour treatment, it has been observed that many tumour cells have developed escape mechanisms against TRAIL-induced apoptosis. As a receptor of LPS, TLR 4, which is expressed on a variety of cancer cells, can be associated with TRAIL-resistance of tumour cells and tumour progression as well as with the generation of an anti-tumour immune response.

METHODS: In this study, the sensitivity to TRAIL-induced apoptosis as well as the influence of LPS-co-stimulation on the cell viability of the pancreatic cancer cell lines PANC-1, BxPC-3 and COLO 357 was examined by FACS analyses and a cell viability assay. Subsequently, the expression of TRAIL-receptors was detected via FACS analyses. Levels of osteoprotegerin (OPG) were also determined using an enzyme-linked immunosorbent assay.

RESULTS: PANC-1 cells were shown to be resistant to TRAIL-induced apoptosis. This was accompanied by significantly increased osteoprotegerin levels and a significantly decreased expression of DR4. In contrast, TRAIL significantly induced apoptosis in COLO 357 cells and to a lesser degree in BxPC-3 cells. Co-stimulation of COLO 357 as well as BxPC-3 cells combining TRAIL and LPS resulted in a significant decrease in TRAIL-induced apoptosis. In COLO 357 cells TRAIL-stimulation decreased the levels of OPG thereby not altering the expression of the TRAIL-receptors 1-4 resulting in a high susceptibility to TRAIL-induced apoptosis. Co-stimulation with LPS and TRAIL completely reversed the effect of TRAIL on OPG levels reaching a 2-fold increase beyond the level of non-stimulated cells resulting in a lower susceptibility to apoptosis. In BxPC-3, TRAIL stimulation decreased the expression of DR4 and significantly increased the decoy receptors TRAIL-R3 and TRAIL-R4 leading to a decrease in TRAIL-induced apoptosis. OPG levels remained unchanged. Co-stimulation with TRAIL and LPS further enhanced the changes in TRAIL-receptor-expression promoting apoptosis resistance.

CONCLUSIONS: Here it has been shown that TRAIL-resistance in pancreatic cancer cells can be mediated by the inflammatory molecule LPS as well as by different expression patterns of functional and non-functional TRAIL-receptors.