Activin and TGFβ use diverging mitogenic signaling in advanced colon cancer.
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 TGFβ or activin-induced metastatic phenotype of colon cancer.


METHODS
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 TGFβ/MEK/ERK pathway activation. Activin, but not TGFβ, led to PI3K activation via interaction of ACVR1B and p85 independent of SMAD4, resulting in p21 downregulation. In contrast, TGFβ increased p21 via MEK/ERK pathway through a SMAD4-dependent mechanism. While activin induced EMT via PI3K, TGFβ induced EMT via MEK/ERK activation. In vivo, loss of ACVR2A resulted in loss of pAkt, consistent with activin-dependent PI3K signaling.


CONCLUSIONS
Although activin and TGFβ 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 TGFβ ligand signaling phenotype warranting further validation as a therapeutic biomarker prior to targeting TGFβ family receptors.
Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, 840 South Wood Street, 738A CSB, Chicago, IL, 60612, USA.
Jessica
J
Bauer
Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, 840 South Wood Street, 738A CSB, Chicago, IL, 60612, USA.
Ozkan
O
Ozden
Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, 840 South Wood Street, 738A CSB, Chicago, IL, 60612, USA.
Naomi
N
Akagi
Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, 840 South Wood Street, 738A CSB, Chicago, IL, 60612, USA.
Timothy
T
Carroll
Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, 840 South Wood Street, 738A CSB, Chicago, IL, 60612, USA.
Daniel R
DR
Principe
Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, 840 South Wood Street, 738A CSB, Chicago, IL, 60612, USA.
Jonas J
JJ
Staudacher
Department of Internal Medicine III, Cardiology and Angiology, University Hospital Schleswig-Holstein, Kiel, Germany.
Martina E
ME
Spehlmann
Department of Medicine, University of California, San Diego, CA, USA.
Lars
L
Eckmann
Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, 840 South Wood Street, 738A CSB, Chicago, IL, 60612, USA.
Paul J
PJ
Grippo
Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, 840 South Wood Street, 738A CSB, Chicago, IL, 60612, USA. bjung@uic.edu.
Barbara
B
Jung
D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism; D028341:Activins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D018125:Receptors, Transforming Growth Factor beta; D028341:Activins; D019869:Phosphatidylinositol 3-Kinases; D030301:Activin Receptors, Type II; C425585:activin receptor type II-A; D016283:Proto-Oncogene Proteins p21(ras)