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

Abstract

Transforming growth factor-beta (TGF-β) and oxidative stress/Reactive Oxygen Species (ROS) both have pivotal roles in health and disease. In this review we are analyzing the interplay between TGF-β and ROS in tumorigenesis and cancer progression. They have contradictory roles in cancer progression since both can have antitumor effects, through the induction of cell death, senescence and cell cycle arrest, and protumor effects by contributing to cancer cell spreading, proliferation, survival, and metastasis. TGF-β can control ROS production directly or by downregulating antioxidative systems. Meanwhile, ROS can influence TGF-β signaling and increase its expression as well as its activation from the latent complex. This way, both are building a strong interplay which can be taken as an advantage by cancer cells in order to increment their malignancy. In addition, both TGF-β and ROS are able to induce cell senescence, which in one way protects damaged cells from neoplastic transformation but also may collaborate in cancer progression. The mutual collaboration of TGF-β and ROS in tumorigenesis is highly complex, and, due to their differential roles in tumor progression, careful consideration should be taken when thinking of combinatorial targeting in cancer therapies.

Figure 1

TGF-β signaling. Active TGF-β1 binds to its cell surface type II receptor (TβRII) inducing the activation of TGF-β type I receptor (ALK5/TβRI) forming a heterotetrameric complex. Active TβRI from the complex then triggers the activation of the Smad pathway: TβRI phosphorylates the receptor associated-Smads (R-Smads) Smad2,3 which in turn promotes their release from the complex with SARA from the inner face of plasma membrane. Phosphorylated Smads interact with co-Smad4 forming a heteromeric complex to be translocated into the cell nucleus, where, through the interaction with other transcription factors and corepressors or coactivators, it modulates gene expression. Active TGF-β-receptors can also activate the non-Smad signaling pathways, such as ERK1,2, p38, JNK, and NF-κB. Furthermore, the active receptor complex can activate PI3K provoking the activation of AKT and the small Rho GTPases. The activation of non-Smad signaling pathways can, in turn, initiate transcriptional or nontranscriptional activity to regulate gene and cellular responses.

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.

Figure 3

TGF-β and ROS cooperate in the induction of epithelial mesenchymal transition. Both TGF-β and ROS are involved in the induction of EMT, as well as their mutual cooperation. TGF-β stimulates ROS production in cancer cells, and the enhancement of ROS levels in turn may induce the activation of extracellular matrix-associated TGF-β latent complex, thus exacerbating TGF-β-induced EMT. Meanwhile, the increment of ROS also stimulates EMT, and both finally may collaborate to induce conversion of the epithelial to the mesenchymal phenotype, thus strengthening tumor progression and metastasis.