Effects of Activin and TGFβ on p21 in Colon Cancer

Abstract

Activin and TGFβ share SMAD signaling and colon cancers can inactivate either pathway alone or simultaneously. The differential effects of activin and TGFβ signaling in colon cancer have not been previously dissected. A key downstream target of TGFβ signaling is the cdk2 inhibitor p21 (p21cip1/waf1). Here, we evaluate activin-specific effects on p21 regulation and resulting functions. We find that TGFβ is a more potent inducer of growth suppression, while activin is a more potent inducer of apoptosis. Further, growth suppression and apoptosis by both ligands are dependent on SMAD4. However, activin downregulates p21 protein in a SMAD4-independent fashion in conjunction with increased ubiquitination and proteasomal degradation to enhance migration, while TGFβ upregulates p21 in a SMAD4-dependent fashion to affect growth arrest. Activin-induced growth suppression and cell death are dependent on p21, while activin-induced migration is counteracted by p21. Further, primary colon cancers show differential p21 expression consistent with their ACVR2/TGFBR2 receptor status. In summary, we report p21 as a differentially affected activin/TGFβ target and mediator of ligand-specific functions in colon cancer, which may be exploited for future risk stratification and therapeutic intervention.

Homozygous deletion of the activin A receptor, type IB gene is associated with an aggressive cancer phenotype in pancreatic cancer

“…Based on numerous previous studies and our data on cellular growth inhibition [22,28], we used concentrations of 0.1, 1, or 10 ng/mL of TGFB1 or 1, 10, or 100 ng/mL of activin A. TGFB1 inhibited cellular growth in the Sui66, Sui68, and Sui73 cell lines (Figure 3B, C, and D). Activin A did not influence cellular growth in the Sui65 and Sui68 cell lines (Figure 3A and C), although it inhibited cellular growth in the Sui66 and Sui73 cell lines (Figure 3B and D).…”

TGFβ Signaling in the Pancreatic Tumor Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis

“…Once biologically available to its target cells, TGFβ binds its type 2 receptor (TGFBR2), leading to the recruitment of its type 1 receptor (TGFBR1) and subsequent downstream signaling that leads to nuclear localization of the SMAD2/3/4 complex. In pancreas epithelial cells, TGFβ affects the cell cycle via upregulation of cyclin-dependent kinase inhibitors, particularly p21 CIP1/WAF1 (3). In advanced tumors, this function is often lost (4) as TGFβ levels begin to correlate positively with recurrence and negatively with disease-free survival (5).…”

Cordycepin induced MA-10 mouse Leydig tumor cell apoptosis by regulating p38 MAPKs and PI3K/AKT signaling pathways

“…Thus, alternative pathways activated by cordycepin may regulate p21 and CDK2. In fact, TGFβ could upregulate p21 through Smad4 44 . Here, cordycepin upregulated TGFβ 2 and Smad4.…”