Open AccessTLR3 induction by anticancer drugs potentiates poly I:C‐induced tumor cell apoptosis
Author(s) -
Taura Manabu,
Fukuda Ryosuke,
Suico Mary Ann,
Eguma Ayaka,
Koga Tomoaki,
Shuto Tsuyoshi,
Sato Takashi,
MorinoKoga Saori,
Kai Hirofumi
Publication year - 2010
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2010.01567.x
Subject(s) - apoptosis , tlr3 , cancer research , programmed cell death , cell culture , interferon , chemistry , biology , receptor , immunology , toll like receptor , biochemistry , innate immune system , genetics
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‐α (IFN‐α) 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‐α 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‐α 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. ( Cancer Sci 2010)