Endoplasmic reticulum oxidoreductase 1 alpha modulates prostate cancer hallmarks

Background: Therapies available for late stage prostate cancer (PCa) patients are limited and mostly palliative. The necessary development of unexplored therapeutic options relies on a deeper knowledge of molecular mechanisms leading to cancer progression. Redox signals are known to modulate the intensity and duration of oncogenic circuits; cues originating from the endoplasmic reticulum (ER) and downstream exocytic organelles are relevant in secretory tumors, including PCa. Ero 1a is a master regulator of redox homeostasis and oxidative folding. Methods: We assessed Ero 1a mRNA expression by bioinformatic analysis of three public datasets and protein expression levels in PCa cell lines representing different degrees of tumor progression and different human prostate specimens. Transient Ero 1a knockdown was achieved by RNA interference (siRNA). Consequences of Ero 1a downregulation were monitored by PCa proliferation, migration and invasion properties. Results: Ero 1a mRNA and protein levels are upregulated in PCa cell lines compared to non-tumorigenic cells (P=0.0273). Ero 1a expression increases with the grade of malignancy, reaching the highest level in the androgen resistant PC3. In patients' samples from 3 datasets, Ero 1a mRNA expression correlates with pathological Gleason scores. Ero 1a knockdown inhibits proliferation (P=0.0081), migration (P=0.0085) and invasion (P=0.0007) of PC3 cells and alters the levels of integrin β1 (P=0.0024). Conclusions: Results indicate that Ero 1a levels correlate with PCa aggressiveness; Ero 1a silencing inhibits key steps over the PCa metastatic process. Therefore, Ero 1a has the potential to be exploited as a novel biomarker and a therapeutic target in PCa.