Abstract
Background: Prostate cancer (PCa) dissemination shows a tendency to develop in the bone, where heme oxygenase 1 (HO-1) plays a critical role in bone remodeling. Previously by LC/ESI-MSMS, we screened for HO-1 interacting proteins and identified annexin 2 (ANXA2). The aim of this study was to analyze the relevance of ANXA2/HO-1 in PCa and bone metastasis. Methods: We assessed ANXA2 levels using a co-culture transwell system of PC3 cells (pre-treated or not with hemin, an HO-1 specific inducer) and the pre-osteoclastic Raw264.7 cell line. Results: Under co-culture conditions, ANXA2 mRNA levels were significantly modulated in both cell lines. Immunofluorescence analysis unveiled a clear ANXA2 reduction in cell membrane immunostaining for Raw264.7 under the same conditions. This effect was supported by the detection of a decrease in Ca2+ concentration in the conditioned medium. HO-1 induction in tumor cells prevented both, the ANXA2 intracellular relocation and the decrease in Ca2+ concentration. Further, secretome analysis revealed urokinase (uPA) as a key player in the communication between osteoclast progenitors and PC3 cells. To assess the clinical significance of ANXA2/HO-1, we performed a bioinformatics analysis and identified that low expression of each gene strongly associated with poor prognosis in PCa regardless of the clinico-pathological parameters assessed. Further, these genes appear to behave in a dependent manner. Conclusions: ANXA2/HO-1 rises as a critical axis in PCa.
Highlights
Prostate cancer (PCa) is one of the most diagnosed cancer in men and the skeletal complications of this disease represent a difficult clinical hurdle to overcome [1,2]
In the metastatic bone site, we demonstrated that heme oxygenase 1 (HO-1) is capable of modulating signaling pathways relevant to skeletal PCa metastasis, such as FoxO/β-catenin and promotes bone remodeling when human tumor cells are transplanted into the femur of SCID mice [13]
We have previously described the HO-1 interactome in PCa through a proteomics approach, identifying HO-1 molecular partners implicated in cell adhesion and cell–cell communication [16]
Summary
Prostate cancer (PCa) is one of the most diagnosed cancer in men and the skeletal complications of this disease represent a difficult clinical hurdle to overcome [1,2]. A positive correlation between Hmox expression and key bone markers was observed in primary mouse osteoblasts (PMOs) [14] These observations highlight the importance of HO-1 expression in bone, for the physiology of bone cells and in the modulation of the communication between PMOs and PCa cells by soluble factors [14]. To assess the clinical significance of ANXA2/HO-1, we performed a bioinformatics analysis and identified that low expression of each gene strongly associated with poor prognosis in PCa regardless of the clinico-pathological parameters assessed. These genes appear to behave in a dependent manner. Conclusions: ANXA2/HO-1 rises as a critical axis in PCa
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