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.
Highlights
Activin is a member of the TGFb superfamily that regulates cell differentiation, proliferation, and apoptosis in many epithelial and mesenchymal cells [1]
No induction of apoptosis with either ligand was observed in SMAD4-null SW480 cells or FET cells following SMAD4 knockdown paralleling the TUNEL experiments (Figure 1B, C). p21 knockdown in SMAD4 wild type FET cells resulted in loss of apoptosis induction (Figure 1D)
We found that a large subset of colon cancers showed loss of nuclear p21, and that this loss was associated with preservation of activin receptor 2 (ACVR2) (Table 1 and Figure 6), suggesting decreased signaling through the SMAD4/p21 axis, but intact activin SMAD4-independent signaling
Summary
Activin is a member of the TGFb superfamily that regulates cell differentiation, proliferation, and apoptosis in many epithelial and mesenchymal cells [1]. We have previously demonstrated high frequency of ACVR2 mutations in MSI-H colon cancer specimens in conjunction with loss of ACVR2 protein expression [6] and showed that ACVR2 loss is associated with larger colon tumors and poor histologic grade [7]. Both ACVR2 and TGFBR2 mutations commonly occur simultaneously in MSI cancers [6], and cell lines can lose both TGFb and activin signaling [8]. Little is known about the distinct contribution of activin signaling to colon cancer development and metastasis and how TGFb and activin signaling effects differ despite identical intracellular SMAD signaling
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