TLR3 induction by anticancer drugs potentiates poly I:C‐induced tumor cell apoptosis
TLR3 induction by anticancer drugs potentiates poly I:C‐induced tumor cell apoptosis
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DOI：
10.1111/j.1349-7006.2010.01567.x
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发表时间：
2010-07
期刊：
影响因子：
5.7
通讯作者：
M. Taura;Ryosuke Fukuda;M. Suico;Ayaka Eguma;Tomoaki Koga;T. Shuto;Takashi Sato;Saori Morino-Koga;H. Kai
中科院分区：
文献类型：
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作者：
M. Taura;Ryosuke Fukuda;M. Suico;Ayaka Eguma;Tomoaki Koga;T. Shuto;Takashi Sato;Saori Morino-Koga;H. Kai
Toll样受体3（TLR 3）已被公认为癌症治疗的新分子靶点，因为TLR 3被其合成配体poly I：C激活直接导致肿瘤细胞死亡。最近，我们报道了肿瘤抑制因子p53在几种肿瘤细胞系中增加TLR 3的表达。另一项研究也表明，干扰素-α（IFN-α）上调TLR 3表达。因此，我们假设各种抗癌药物如p53激活剂和IFN可能通过上调TLR 3表达增强poly I：C诱导的肿瘤细胞死亡。在这里，我们筛选了几种抗癌药物，连同聚I：C，有效地导致肿瘤细胞死亡的结肠癌HCT 116细胞。我们发现，DNA损伤试剂5-氟尿嘧啶（5-FU）增加了HCT 116 p53+/+细胞中TLR 3 mRNA的表达，并增强了poly I：C诱导的凋亡，但对p53−/−细胞的影响很小，表明p53依赖性途径。另一方面，IFN-α增加了HCT 116 p53+/+和p53−/−细胞系中poly I：C诱导的凋亡和TLR 3 mRNA水平。此外，poly I：C、5-FU和IFN-α的组合在HCT 116 p53+/+和p53−/−细胞中诱导了最高的凋亡。总之，这些数据表明，抗癌药物增加了TLR 3表达，随后可能通过p53依赖性和非依赖性途径增强了poly I：C诱导的细胞凋亡。考虑到恶性细胞中的p53状态是异质性的，这种组合方法可以提供高效的肿瘤治疗。（Cancer Sci 2010）
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)