Multiple Factors Determine the Oncolytic or Carcinogenic Effects of TLRs Activation in Cancer

Figure 1

Cell surface TLRs signal pathway. TLR2/6 is used as an example to elaborate this pathway. Upon sensing corresponding ligand, cell surface TLR dimerizes and combines with TIRAP/Mal. The adaptor protein MyD88 binds to IRAK4. This causes binding of IRAK1 and IRAK2. Thus, a highly ordered signaling complex, myddosome is formed. Myddosome contains six to eight MyD88, four IRAK4, and four IRAK2. The activated IRAKs then combines with TRAF6 which assembles polyubiquitin chains. These chains connect and ubiquitinate transforming growth factor β-activated kinase-1 (TAK1), transforming growth factor β-activated kinase-1-binding protein-1 (TAB1), and NF-κB essential modulator (NEMO) (consisting of IKKα, IKKβ, and IKKγ). Activated TAK1 and NEMO phosphorylate IκB. This results in IκB phosphorylation and degradation. Without the inhibition of IκB, NF-κB translocates into the nucleus to induce the transcription of proinflammatory cytokines. TRAF6 is also capable of activating TRAF3 and inducing IL-10 production. Activated TRAF3 can bind TRAF family member-associated NF-κB activator-binding kinase 1 (TBK1) to the myddsome to induce glycolysis and Type I IFN expression via IRF3.