Targeting SMAD-Dependent Signaling: Considerations in Epithelial and Mesenchymal Solid Tumors

Abstract

SMADs are the canonical intracellular effector proteins of the TGF-β (transforming growth factor-β). SMADs translocate from plasma membrane receptors to the nucleus regulated by many SMAD-interacting proteins through phosphorylation and other post-translational modifications that govern their nucleocytoplasmic shuttling and subsequent transcriptional activity. The signaling pathway of TGF-β/SMAD exhibits both tumor-suppressing and tumor-promoting phenotypes in epithelial-derived solid tumors. Collectively, the pleiotropic nature of TGF-β/SMAD signaling presents significant challenges for the development of effective cancer therapies. Here, we review preclinical studies that evaluate the efficacy of inhibitors targeting major SMAD-regulating and/or -interacting proteins, particularly enzymes that may play important roles in epithelial or mesenchymal compartments within solid tumors.

Advances and Challenges in Targeting TGF-β Isoforms for Therapeutic Intervention of Cancer: A Mechanism-Based Perspective

“…It is rapidly deactivated through the concerted actions of inhibitory Smad7, the targeted degradation of TGF-β receptors and Smads via ubiquitin ligases like HECT, Smurfs, ROC-1, and Arkadia [ 213 , 214 , 215 , 216 ], as well as the deactivation of R-Smads mediated by the nuclear phosphatase PPM1A ( Figure 3 ) [ 217 ]. Readers are referred to a recent review by Runa et al [ 218 ] for a more in-depth look at the post-translation control and nuclear uptake of Smads in cancer.…”