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

Abstract

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 betaA-subunit of activin A and phospho-GSKalpha/beta (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 betaA 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-GSKalpha/beta (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-GSKalpha/beta (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.

Activin A inhibits RANKL-mediated osteoclast formation, movement and function in murine bone marrow macrophage cultures

“…8A,B) with MCSF, MCSF plus RANKL, MCSF plus ActA or all three reagents combined. ActA signals through both SMAD-dependent and SMAD-independent pathways, including the activation of AKT1 (Do et al, 2008). Therefore, immunoblot analysis was performed to determine the effects of ActA on SMAD2 Fig.…”

Activin A, B and AB decrease progesterone production by down-regulating StAR in human granulosa cells

“…However, intracellular cascades other than SMAD have been shown to mediate the signaling triggered by activins. Specifically, mitogen-activated protein kinase (MAPK) family members, including Akt kinase (Do et al, 2008), c-Jun N-terminal kinases (JNKs) (Zhang et al, 2005) and p38 kinase (de Guise et al, 2006), have been demonstrated to act downstream of the activin ligand-receptor complex. Collectively, activin-induced activation of differential responses may lead to both SMAD-dependent and SMAD-independent signaling pathways in a cell-specific manner (Derynck and Zhang, 2003).…”

Biomolecular Pathogenesis of Borderline Ovarian Tumors: Focusing Target Discovery Through Proteogenomics

“…In ovarian cancer patients, both phosphorylated JAK2 and activated STAT3 showed higher expression in high grade tumors respect to normal ovaries and borderline tumors [69]. The two cancer cell lines OVCA 433 and SKOV3 treated with EGF down-regulated the expression of epithelial-restricted E-cadherin and increased the expression of vimentin and 2, 6 1 integrin subunits [71].…”

“…In ovarian cancer, A expression was elevated in stromal cells from carcinomas. Moreover, a different GSK-phosphorylation status was identified in benign cystadenomas, borderline tumors, and carcinomas [69].…”