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The Role of Activin A and Akt/GSK Signaling in Ovarian Tumor Biology

Departments of Obstetrics and Gynecology (T.-V.D., M.A., T.K.W.), of Pathology (L.A.K., C.D.S.), and of Preventive Medicine (A.W.R.), and Robert H. Lurie Cancer Center (A.W.R., T.K.W.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611-3008; Center for Reproductive Science (T.-V.D., M.A., T.K.W.), Northwestern University, Evanston, Illinois 60208; and Department of Pathology (L.A.K., C.D.S.), Evanston Northwestern Healthcare, Evanston, Illinois 60201

Address all correspondence and requests for reprints to: Teresa K. Woodruff, Ph.D., Northwestern University, 2205 Tech Drive/Hogan 4-150, Evanston, Illinois 60208. E-mail: tkw{at}northwestern.edu.

Elevated activin A levels in serum, cyst fluid, and peritoneal fluid of ovarian cancer patients suggest a role for this peptide hormone in disease development. We hypothesize that activin A plays a role in ovarian tumor biology, and analyzed activin-mediated pro-oncogenic signaling in vitro and the expression of activin signaling pathway molecules in vivo. Activin A regulation of Akt and GSK, and the effects of repressing the activities of these molecules (with pharmacological inhibitors) on cellular proliferation were assessed in the cell line, OVCA429. Activin A activated Akt, which phosphorylated GSK, repressing GSK activity in vitro. Activin A stimulated cellular proliferation and repression of GSK augmented activin-regulated proliferation. To validate in vitro observations, immunostaining of the βA-subunit of activin A and phospho-GSK/β (Ser9/21) was performed, and the correlation between immunoreactivity levels of these markers and survival was evaluated in benign serous cystadenoma, borderline tumor, and cystadenocarcinoma microarrays. Analysis of tissue microarrays revealed that βA expression in epithelia did not correlate with survival or malignancy, but expression was elevated in stromal cells from carcinomas when compared with benign tumors. Phospho-GSK/β (Ser9/21) staining was more intense in mitotically active carcinoma cells and exhibited a polarized localization in benign neoplasms that was absent in carcinomas. Notably, lower phospho-GSK/β (Ser9/21) immunoreactivity correlated with better survival for carcinoma patients (P = 0.046). Our data are consistent with a model in which activin A may mediate ovarian oncogenesis by activating Akt and repressing GSK to stimulate cellular proliferation.