TGF-beta signaling and the role of inhibitory Smads in non-small cell lung cancer

Abstract

The signaling pathway mediated by transforming growth factor-beta (TGF-beta) participates in various biologic processes, including cell growth, differentiation, angiogenesis, apoptosis, and extracellular matrix remodeling. In the context of cancer, TGF-beta signaling can inhibit tumor growth in early-stage tumors. However, in late-stage tumors, the very same pathway promotes tumor invasiveness and metastasis. This paradoxical effect is mediated through similar to mothers against decapentaplegic or Smad protein dependent and independent mechanisms and provides an opportunity for targeted cancer therapy. This review summarizes the molecular process of TGF-beta signaling and the changes in inhibitory Smads that contribute to lung cancer progression. We also present current approaches for rational therapies that target the TGF-beta signaling pathway in cancer.

FIGURE 1

Schematic diagram of transforming growth factor-β (TGF-β) signaling pathway. TGF-β signaling is initiated by the binding of TGF-β to its receptors, transforming growth factor-β receptor I (TGF-β RI) and transforming growth factor-β receptor II (TGF-β RII), and receptor tyrosine kinase activation which then phosphorylates Smad2/3. Activated Smad2/3 regulates gene expression of Smad4 and other transcription factors (TF). Feedback regulation is mediated by Smad6/7, which interferes the binding of Smad2/3 to TGF-β receptors and inhibits transcription. Both Smad6 and Smad7 are in turn induced by TGF-β and regulated by Smad ubiquitin regulatory factors (Smurfs). Synthetic inhibitors inactivate the TGF-β pathway by inhibition of receptor enzymatic activity.