title: TLR3 induction by anticancer drugs potentiates poly I:C-induced tumor cell apoptosis.
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.
authors.affiliation: Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Global COE Cell Fate Regulation Research and Education Unit, Kumamoto University, Kumamoto, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Taura
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Fukuda
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Suico
authors.forename: Ayaka
authors.initials: A
authors.lastname: Eguma
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Koga
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shuto
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.forename: Saori
authors.initials: S
authors.lastname: Morino-Koga
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kai
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D016899:Interferon-beta / Q000494:pharmacology; D007668:Kidney; D008175:Lung Neoplasms / Q000235:genetics; D051379:Mice; D011070:Poly I-C / Q000235:genetics / Q000494:pharmacology*; D051196:Toll-Like Receptor 3 / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D016898:Interferon-alpha; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D016899:Interferon-beta; D011070:Poly I-C; D005472:Fluorouracil