p21 plays a complex role in cancer. Tumor suppressive properties of p21 have been described in the context of induction of growth http://www.selleckchem.com/products/AP24534.html arrest, differentiation and senescence and studies in different cancer types showed that p21 expression correlates with a favorable diagnosis [10]. Consistent with the above finding, several studies in colon cancer revealed an association between p21 downregulation and metastasis as well as poor survival [30], [31], [32] [33], however, some reports point towards a dual role in several cancers with increase of p21 correlating with poor outcome [34], [35]. Here, we report a substantial number of primary colon cancers with loss of nuclear p21, which correlates with presence of ACVR2 and absence of TGFBR2.

This is in line with our in vitro data where we show downregulation of p21 in the context of enhanced SMAD4-independent signaling induced by activin. It is also consistent with the concept of an absent upregulation of p21 after abrogation of the TGF��/SMAD4 axis, which can be explained by knockdown of SMAD4, as in our experiments, but also by absence of TGFBR2, as seen in the cancer samples. The functional consequences we would expect from decreased p21 levels in conjunction with preservation of ACVR2 and loss of TGFBR2 based on our data are enhanced migration via SMAD4-independent signaling and loss of growth suppression through the TGF��/SMAD4/p21 axis. Independent of the effect on growth suppression, which alone has been found to be a weak prognostic marker in many cancers [36], the ACVR2+/TGFBR2- receptor status associated with loss of nuclear p21 points to a pro-metastatic and thus more aggressive cancer phenotype.

This is consistent with previous findings showing that loss of p21 is associated with worse outcome in various cancer types [10]. While other signaling pathways may direct p21 localization, our data establish the basis for further assessment of activin and TGF�� receptor status in association with p21 localization for prediction of outcome and response to therapy in colon cancer. In summary, our data show that TGF�� 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 and p21. However, activin downregulates nuclear and total p21 protein in a SMAD4-independent fashion in conjunction with increased ubiquitination Entinostat and proteasomal degradation associated with enhanced migration. TGF�� on the other hand upregulates nuclear p21 in a SMAD4-dependent fashion to affect growth arrest and may bypass p21 to affect migration.