Autophagy facilitates TLR4-and TLR3-triggered migration and invasion of lung cancer cells through the promotion of TRAF6 ubiquitination
Autophagy facilitates TLR4-and TLR3-triggered migration and invasion of lung cancer cells through the promotion of TRAF6 ubiquitination
复制标题
自噬通过促进TRAF6泛素化促进TLR4和TLR3触发的肺癌细胞迁移和侵袭
DOI：
10.4161/auto.27162
复制
发表时间：
2014-02-01
期刊：
影响因子：
13.3
通讯作者：
Liu, Zhongmin
中科院分区：
文献类型：
--
作者：
Zhan, Zhenzhen;Xie, Xuefeng;Liu, Zhongmin
自噬有助于癌症的发病机制，而Toll样受体（TLR）也在癌症发展和免疫逃逸中发挥重要作用。然而，关于TLR信号传导和癌细胞自噬之间的潜在相互作用知之甚少。在这里，我们发现TLR 4或TLR 3激活诱导的自噬通过促进TRAF 6（TNF受体相关因子6，E3泛素蛋白连接酶）泛素化增强各种细胞因子的产生，从而促进肺癌细胞的迁移和侵袭。TLR 4和TLR 3分别用脂多糖（LPS）和聚肌胞苷酸[poly（I：C）]刺激触发肺癌细胞的自噬。这是介导的衔接蛋白，toll样受体衔接分子1（TICAM 1/TRIF），并且是TLR 4和TLR 3诱导的IL 6、CCL 2/MCP-1 [趋化因子]产生增加所必需的。（C-C基序）配体2]、CCL 20/MIP-3 [趋化因子（C-C基序）配体20]、VEGFA（血管内皮生长因子A）和MMP 2 [基质金属肽酶2（明胶酶A、72 kDa明胶酶、72 kDa IV型胶原酶）]。这些细胞因子似乎是增强TLR激活后肺癌细胞的迁移和侵袭所必需的。值得注意的是，通过化学或遗传方法抑制自噬阻断了TLR 4或TLR 3诱导的TRAF 6的Lys 63（K63）连接的泛素化，这对于MAPK和NF κ B（B细胞中κ轻链多肽基因增强子的核因子）途径的激活是必需的，这两者都参与了细胞因子的产生增加。总的来说，这些结果将TLR 4和TLR 3诱导自噬确定为驱动肺癌进展的重要机制，并表明抑制自噬可能是治疗肺癌的有用策略。
Autophagy contributes to the pathogenesis of cancer, whereas toll-like receptors (TLRs) also play an important role in cancer development and immune escape. However, little is known about the potential interaction between TLR signaling and autophagy in cancer cells. Here we show that autophagy induced by TLR4 or TLR3 activation enhances various cytokine productions through promoting TRAF6 (TNF receptor-associated factor 6, E3 ubiquitin protein ligase) ubiquitination and thus facilitates migration and invasion of lung cancer cells. Stimulation of TLR4 and TLR3 with lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid [poly(I:C)] respectively triggered autophagy in lung cancer cells. This was mediated by the adaptor protein, toll-like receptor adaptor molecule 1 (TICAM1/TRIF), and was required for TLR4- and TLR3-induced increases in the production of IL6, CCL2/MCP-1 [chemokine (C-C motif) ligand 2], CCL20/MIP-3 [chemokine (C-C motif) ligand 20], VEGFA (vascular endothelial growth factor A), and MMP2 [matrix metallopeptidase 2 (gelatinase A, 72 kDa gelatinase, 72 kDa type IV collagenase)]. These cytokines appeared to be necessary for enhanced migration and invasion of lung cancer cells upon TLR activation. Remarkably, inhibition of autophagy by chemical or genetic approaches blocked TLR4- or TLR3-induced Lys63 (K63)-linked ubiquitination of TRAF6 that was essential for activation of MAPK and NFKB (nuclear factor of kappa light polypeptide gene enhancer in B-cells) pathways, both of which were involved in the increased production of the cytokines. Collectively, these results identify induction of autophagy by TLR4 and TLR3 as an important mechanism that drives lung cancer progression, and indicate that inhibition of autophagy may be a useful strategy in the treatment of lung cancer.