Prostate cancer (PCa) is the second leading cause of cancer death in men. Although previous studies in PCa have focused on cell adherens junctions (AJs), key players in metastasis, they have left the molecular mechanisms unexplored. Inflammation and the involvement of reactive oxygen species (ROS) are critical in the regulation of cell adhesion and the integrity of the epithelium. Heme oxygenase-1 (HO-1) counteracts oxidative and inflammatory damage. Here, we investigated whether HO-1 is implicated in the adhesive and morphological properties of tumor cells. Genes differentially regulated by HO-1 were enriched for cell motility and adhesion biological processes. HO-1 induction, increased E-cadherin and β-catenin levels. Immunofluorescence analyses showed a striking remodeling of E-cadherin/β-catenin based AJs under HO-1 modulation. Interestingly, the enhanced levels of E-cadherin and β-catenin coincided with a markedly change in cell morphology. To further our analysis we sought to identify HO-1 binding proteins that might participate in the regulation of cell morphology. A proteomics approach identified Muskelin, as a novel HO-1 partner, strongly implicated in cell morphology regulation. These results define a novel role for HO-1 in modulating the architecture of cell-cell interactions, favoring a less aggressive phenotype and further supporting its anti-tumoral function in PCa.
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 Ca 2+ concentration in the conditioned medium. HO-1 induction in tumor cells prevented both, the ANXA2 intracellular relocation and the decrease in Ca 2+ 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.Biomolecules 2020, 10, 467 2 of 24 microenvironment communicate and interact with each other to develop a fertile niche for the promotion of the metastatic process [3][4][5].Evidence has recognized inflammation as a risk factor for this neoplastic disease [6]. Heme oxygenase 1 (HO-1), encoded by the HMOX1 gene, is a stress response protein and a critical mediator of cellular homeostasis [7]. Although the role of HO-1 in cancer is controversial [8,9], we have shown that its pharmacologic or genetic upregulation is associated with a less aggressive phenotype in PCa [10]. HO-1 impairs tumor growth and angiogenesis in vivo and downregulates the expression of target genes associated with inflammation in PCa [11,12]. In the metastatic bone site, we demonstrated that 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]. Moreover, we have shown the direct effect of HO-1 on bone turnover and remodeling. When assessing the physiological impact of Hmox1 gene knockout on bone metabolism in vivo, histomorphometric analysis of Hmox1−/− mice bones exhibited significantly decreased bone density. A positive correlation between Hmox1 expression and key bone markers was observed in primary mouse osteoblasts (PMOs) [14]. These observations highlight the importance of HO-1 expression in bone, not only for the physiology of bone cells but also in the modulation of the communication between PMOs and PC...
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