Abstract
BackgroundAnnexin A2 is increased in serous ovarian cancer and plays an essential role in ovarian cancer invasion and metastasis. In combination with S100A10, annexin A2 plays an important role in the plasminogen activator system regulating plasmin production. The aim of this study was to investigate the potential utility of all-trans retinoid acid (ATRA), an inhibitor of the annexin A2-S100A10 signalling pathway, as a new therapeutic against serous ovarian cancer.MethodsIn this study we determined the effects of ATRA treatment (1-5 μM) on annexin A2 and S100A10 expression, plasmin activation, and the ability of ATRA to inhibit serous ovarian cancer cell survival, motility and invasion in vitro. We also employed an ex vivo tissue explant assay to assess response to ATRA treatment in serous ovarian cancers. Cryopreserved serous ovarian cancer tissues were cultured on gelatin sponges for 72 h with ATRA (1 μM). Effects on apoptosis and proliferation were assessed by immunohistochemistry using antibodies to cleaved caspase 3 or Ki67, respectively.ResultsSurvival of serous ovarian cancer cells (OVCAR-3, OV-90, & OAW28) was significantly decreased by ATRA treatment (1-5 μM). ATRA (1 μM) also significantly decreased proliferation (Ki67 positivity, p = 0.0034), S100A10 protein levels (p = 0.0273), and increased cell apoptosis (cleaved caspase-3 positivity, p = 0.0024) in serous ovarian cancer tissues using the ex vivo tissue explant assay. In OAW28 cells, reduced cell survival following ATRA treatment was associated with a reduction of S100A10 mRNA and protein levels, S100A10 and annexin A2 membrane localization, plasmin generation, motility and invasion. In contrast, ATRA inhibited OV-90 cell survival and invasion but did not affect plasmin activation or S100A10 and annexin A2 expression or membrane localization.ConclusionsThese findings suggest that ATRA inhibits serous ovarian cancer proliferation and invasion via both S100A10 dependant and S100A10 independent mechanisms. Our results show that ATRA has promising potential as a novel therapy against serous ovarian cancer that warrants further evaluation.
Highlights
Annexin A2 is increased in serous ovarian cancer and plays an essential role in ovarian cancer invasion and metastasis
Effects of all-trans retinoid acid (ATRA) treatment on serous ovarian cancer cell survival Survival of OVCAR-3 (Fig. 1a), OAW28 (Fig. 1b) and OV-90 (Fig. 1e) cells was significantly reduced after 6 days of ATRA (5 μM) treatment but no significant effects were observed on COV318 (Fig. 1c) or COV362 cells (Fig. 1d)
Response to ATRA treatment in the ovarian cancer cell lines did not correlate with expression of ANXA2, S100A10 or retinoic acid receptor alpha (RARA) as all cell lines exhibited similar gene expression levels (Additional file 3: Figure S1a)
Summary
Annexin A2 is increased in serous ovarian cancer and plays an essential role in ovarian cancer invasion and metastasis. In combination with S100A10, annexin A2 plays an important role in the plasminogen activator system regulating plasmin production. To identify novel therapeutic targets involved in ovarian cancer metastasis, our laboratory investigated the interaction of ovarian cancer and peritoneal cells using proteomics [6, 7]. The interaction between annexin A2, S100A10 and tissue plasminogen activator (t-PA) mediates the conversion of plasminogen to plasmin which facilitates the extracellular matrix (ECM) degradation, matrix metalloproteinase (MMP) activation, epithelial to mesenchymal transition (EMT) and angiogenesis, leading to increased cancer cell migration and invasion [8, 15, 16]
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