title: 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: Research Center for Translational Medicine & Institute of Heart Failure; East Hospital; Tongji University School of Medicine; Shanghai, China.
authors: Zhenzhen
authors: Z
authors: Zhan
authors: School of Pharmacology; Anhui Medical University; Hefei, Anhui, China.
authors: Xuefeng
authors: X
authors: Xie
authors: Department of Cardiac Surgery; East Hospital; Tongji University School of Medicine; Shanghai, China.
authors: Hao
authors: H
authors: Cao
authors: Research Center for Translational Medicine & Institute of Heart Failure; East Hospital; Tongji University School of Medicine; Shanghai, China.
authors: Xiaohui
authors: X
authors: Zhou
authors: School of Medicine and Public Health; University of Newcastle; NSW, Australia.
authors: Xu Dong
authors: XD
authors: Zhang
authors: Research Center for Translational Medicine & Institute of Heart Failure; East Hospital; Tongji University School of Medicine; Shanghai, China; Department of Cardiac Surgery; East Hospital; Tongji University School of Medicine; Shanghai, China.
authors: Huimin
authors: H
authors: Fan
authors: Research Center for Translational Medicine & Institute of Heart Failure; East Hospital; Tongji University School of Medicine; Shanghai, China; Department of Cardiac Surgery; East Hospital; Tongji University School of Medicine; Shanghai, China.
authors: Zhongmin
authors: Z
authors: Liu
mesh_terms: D001343:Autophagy / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness; D015398:Signal Transduction / Q000502:physiology; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D048029:TNF Receptor-Associated Factor 6; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4
keywords: TRAF6; autophagy; invasion; lung cancer cells; migration; toll-like receptors