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Cancer Sci. 2010 Jul;101(7):1610-7. doi: 10.1111/j.1349-7006.2010.01567.x. Epub 2010 Mar 13.

TLR3 induction by anticancer drugs potentiates poly I:C-induced tumor cell apoptosis.

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1
Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE Cell Fate Regulation Research and Education Unit, Kumamoto University, Kumamoto, Japan.

Abstract

Toll-like receptor 3 (TLR3) has gained recognition as a novel molecular target for cancer therapy because TLR3 activation by its synthetic ligand poly I:C directly causes tumor cell death. Recently, we reported that tumor suppressor p53 increases the expression of TLR3 in several tumor cell lines. Another study also showed that interferon-alpha (IFN-alpha) up-regulates TLR3 expression. We thus hypothesized that various anticancer drugs such as p53-activating reagents and IFNs may potentiate poly I:C-induced tumor cell death through the up-regulation of TLR3 expression. Here, we screened several anticancer drugs that, together with poly I:C, effectively cause tumor cell death in colon carcinoma HCT116 cells. We found that the DNA-damaging reagent 5-fluorouracil (5-FU) increased TLR3 mRNA expression and potentiated poly I:C-induced apoptosis in HCT116 p53(+/+) cells but had only minimal effect in p53(-/-) cells, indicating a p53-dependent pathway. On the other hand, IFN-alpha increased poly I:C-induced apoptosis and the TLR3 mRNA level in HCT116 p53(+/+) and p53(-/-) cell lines. Furthermore, the combination of poly I:C, 5-FU and IFN-alpha induced the highest apoptosis in HCT116 p53(+/+) and p53(-/-) cells. Taken together, these data suggest that the anticancer drugs increased TLR3 expression and subsequently potentiated poly I:C-induced apoptosis likely via p53-dependent and -independent pathways. Considering that the p53 status in malignant cells is heterogeneous, this combination approach may provide a highly effective tumor therapy.

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