Multiple effects of TRAIL in human carcinoma cells: Induction of apoptosis, senescence, proliferation, and cytokine production

Abstract

TRAIL is a death ligand that induces apoptosis in malignant but not normal cells. Recently the ability of TRAIL to induce proliferation in apoptosis-resistant normal and malignant cells was reported. In this study, we analyzed TRAIL effects in apoptosis sensitive MCF7, OVCAR3 and H460 human tumor cell lines. TRAIL at low concentrations preferentially induced cell proliferation. At 100 ng/ ml apoptotic death was readily observed, however surviving cells acquired higher proliferative capacity. TRAIL stimulated production of several cytokines, IL-8, RANTES, MCP-1 and bFGF, and activation of caspases 1 and 8 was essential for this effect. Antibodies to IL-8, RANTES, and bFGF blocked TRAIL-induced cell proliferation and further stimulated apoptosis. For the first time, we report that high TRAIL concentrations induced cell senescence as determined by altered morphology and expression of several senescence markers: SA-β-gal, p21 Waf1/Cip1 , p16 INK4a , and HMGA. Caspase 9 inhibition protected TRAIL-treated cells from senescence, whereas inhibition of caspases 1 and 8 increased yield of SLP cells. In conclusion, in cultured human carcinoma cells, TRAIL therapy results in three functional outcomes, apoptosis, proliferation and senescence. TRAIL induced proapoptotic and prosurvival responses correlate with strength of signaling. TRAIL-induced cytokine production is responsible for its proliferative and prosurvival effects.

Inability of Plasmacytoid Dendritic Cells To Directly Lyse HIV-Infected Autologous CD4 + T Cells despite Induction of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand

“…Studies of acute infection in humans have also shown a severe loss of circulating PDC, with conflicting data regarding sustained plasma IFN-␣ levels, which are expected to be transiently increased, as observed in SIV infection. Once chronic infection is established, a decrease in IFN-␣ production from PDC in spite of increased accumulation of IFN-␣ mRNA in the remaining circulating PDC has been described (50). With regard to TRAIL expression, we document its induction in PDC and association with viral replication yet do not document a relationship with increasing type I interferon plasma levels (IFN-␣ or IFN-␤).…”

“…Besides apoptosis induction, TRAIL has also been shown to have antiapoptotic (prosurvival), regulatory, and proliferative functions (7,21,50,64,73), and its role in HIV infections is likely to be more complex than proposed. Interestingly, a recent report by Shepard et al clearly showed the beneficial effect of TRAIL by demonstrating a reduction in viral load without significant death of bystander cells (65).…”

The pleiotropic effect of TRAIL on tumor-like synovial fibroblasts from rheumatoid arthritis patients is mediated by caspases

“…22 Multiple effects of TRAIL have been earlier reported in human carcinoma cell lines. 23 Low concentrations of TRAIL (1 ng/ml) were found to preferentially induce proliferation in human carcinoma cells. At higher concentrations (100 ng/ml), the situation was more complex, as cell populations responded with either apoptosis, senescence or proliferation.…”

Dual Effects of TRAIL in Suppression of Autoimmunity: The Inhibition of Th1 Cells and the Promotion of Regulatory T Cells

“…With regard to the relationship between TRAIL and Tregs, TRAIL was shown to expand CD4 + CD25 + Tregs in a study of experimental autoimmune thyroiditis (EAT) (20). With regard to the ability of TRAIL to induce cell proliferation, it was recently reported that TRAIL promotes the proliferation of vascular smooth muscle cells and carcinoma cells (21,22).…”