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-a (IFN-a) 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 p53indicating a p53-dependent pathway. On the other hand, IFN-a 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-a 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.

Aptamer-Mediated Blockade of IL4Rα Triggers Apoptosis of MDSCs and Limits Tumor Progression

“…[24][25][26][27][28] or activation of RNA-dependent protein kinase (PKR; refs. [29][30][31][32][33].…”

The Role of Inflammation in Cancer

“…It is the most potent type 1 interferon stimulant that is recognised by TLR3 (Yoneyama, 2004;Matsumoto, 2008). TLR3 stimulation by dsRNA can cause direct apoptosis and inhibit cell proliferation in various types of cancer cells including colon, breast and melanoma (Taura, 2010;Salaun, 2006Salaun, , 2007. It is now known that expression and function of TLR3 is dependent on p53 activation (Taura, 2008).…”

“…Interferons (IFN) are a group of cytokines that can cause antiviral, antiproliferative and apoptotic effects through the Jak/STAT pathway signal transducers (Stark, 2007). In particular, IFN-, a type I IFN has been shown to induce TLR3 expression and thus significantly enhance tumour cell apoptosis when combined with Poly I:C compared to each treatment alone (Taura 2010). The same study combined IFN-, Poly I:C and 5-FU which resulted in a significant increase in cancer cell death in a colon cancer cell line.…”

Immunotherapy in Urologic Malignancies: The Evolution and Future of Pattern Recognition Receptors

“…Activation of TLRs in various tumor lines and models has shown both evidence of tumor reduction and cancer progression (Maruyama et al, 2011). In prostate and kidney cancer cell lines, TLR3 activation has been shown to induce apoptosis, while TLR9 has been shown to promote prostate cancer invasion, and IL-8 and TGF production in vitro (Di et al, 2009;Ilvesaro et al, 2007;Paone et al, 2008;Taura et al, 2010). In bladder cancer lines, elevated expression of TLR2-4, 5, 7, and 9 was detected in non-muscle invasive tumors, with decreased expression in muscle invasive tumors (Ayari et al, 2011).…”