Activin and TGF beta use diverging mitogenic signaling in advanced colon cancer

作者：Bauer Jessica; Ozden Ozkan; Akagi Naomi; Carroll Timothy; Principe Daniel R; Staudacher Jonas J; Spehlmann Martina E; Eckmann Lars; Grippo Paul J; Jung Barbara

来源：Molecular Cancer, 2015, 14(1): 182.

DOI：10.1186/s12943-015-0456-4

• Colon cancer
• Activin
• TGF beta
• PI3K
• Mitogenic signaling
• p21

Background: Understanding cell signaling pathways that contribute to metastatic colon cancer is critical to risk stratification in the era of personalized therapeutics. Here, we dissect the unique involvement of mitogenic pathways in a TGF beta or activin-induced metastatic phenotype of colon cancer.
Method: Mitogenic signaling/growth factor receptor status and p21 localization were correlated in primary colon cancers and intestinal tumors from either AOM/DSS treated ACVR2A (activin receptor 2) -/- or wild type mice. Colon cancer cell lines (+/- SMAD4) were interrogated for ligand-induced PI3K and MEK/ERK pathway activation and downstream protein/phospho-isoform expression/association after knockdown and pharmacologic inhibition of pathway members. EMT was assessed using epithelial/mesenchymal markers and migration assays.
Results: In primary colon cancers, loss of nuclear p21 correlated with upstream activation of activin/PI3K while nuclear p21 expression was associated with TGF beta/MEK/ERK pathway activation. Activin, but not TGF beta, led to PI3K activation via interaction of ACVR1B and p85 independent of SMAD4, resulting in p21 downregulation. In contrast, TGF beta increased p21 via MEK/ERK pathway through a SMAD4-dependent mechanism. While activin induced EMT via PI3K, TGF beta induced EMT via MEK/ERK activation. In vivo, loss of ACVR2A resulted in loss of pAkt, consistent with activin-dependent PI3K signaling.
Conclusion: Although activin and TGF beta share growth suppressive SMAD signaling in colon cancer, they diverge in their SMAD4-independent pro-migratory signaling utilizing distinct mitogenic signaling pathways that affect EMT. p21 localization in colon cancer may determine a dominant activin versus TGF beta ligand signaling phenotype warranting further validation as a therapeutic biomarker prior to targeting TGF beta family receptors.

• 出版日期2015-10-24