Autophagy facilitates TLR4- and TLR3-triggered migration and invasion of lung cancer cells through the promotion of TRAF6 ubiquitination.

Abstract

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-3α [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.

• Authors: Zhenzhen Zhan, Xuefeng Xie, Hao Cao, Xiaohui Zhou, Xu Dong Zhang, Huimin Fan, Zhongmin Liu
• Journal: Autophagy (Autophagy) Vol. 10 Issue 2 Pg. 257-68 (Feb 2014) ISSN: 1554-8635 [Electronic] United States
• PMID: 24321786 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Lipopolysaccharides
• TLR3 protein, human
• TLR4 protein, human
• TNF Receptor-Associated Factor 6
• Toll-Like Receptor 3
• Toll-Like Receptor 4

Topics

• Autophagy (physiology)
• Cell Line, Tumor
• Cell Movement
• Cytokines (metabolism)
• Humans
• Lipopolysaccharides (pharmacology)
• Lung Neoplasms (metabolism, pathology)
• Neoplasm Invasiveness
• Signal Transduction (physiology)
• TNF Receptor-Associated Factor 6 (metabolism)
• Toll-Like Receptor 3 (metabolism)
• Toll-Like Receptor 4 (metabolism)
• Ubiquitination (physiology)