Review Article

Transforming Growth Factor-Beta and Oxidative Stress Interplay: Implications in Tumorigenesis and Cancer Progression

Figure 2

TGF-β and ROS interplay. TGF-β is synthesized as an inactive precursor protein. The signal peptide (SP), which leads the TGF-β precursor protein through its secretory pathway, is cleaved during the transit through the rough endoplasmic reticulum (RER), this way forming a protein homodimer. Its cleavage by furin convertase produces the small latent complex (SLC) in which mature TGF-β remains noncovalently bound to latency-associated peptide (LAP). Next, SLC by covalent binding to latent TGF-β binding protein (LTBP) produces the large latent complex (LLC). Finally, LLC is secreted and stored in the extracellular matrix for subsequent activation. The increased levels of ROS induce the release and bioavailability of TGF-β from the LLC through the oxidative modification of LAP. Active TGF-β by binding to its cell surface receptors induces the activation of downstream pathways, which further regulate ROS production by both NOX activation and increased NOX expression or by downregulation of antioxidative proteins expression. In addition, increased ROS production may directly induce TGF-β expression.