Abstract
Prostate cancer (PCa) cells display abnormal expression of proteins resulting in an augmented capacity to resist chemotherapy and colonize distant organs. We have previously shown the anti-tumoral role of heme oxygenase 1 (HO-1) in this disease. In this work, we undertook a mass spectrometry-based proteomics study to identify HO-1 molecular interactors that might collaborate with its modulatory function in PCa. Among the HO-1 interactors, we identified proteins with nuclear localization. Correlation analyses, using the PCa GSE70770 dataset, showed a significant and positive correlation between HMOX1 and 6 of those genes. Alternatively, HMOX1 and YWHAZ showed a negative correlation. Univariable analyses evidenced that high expression of HNRNPA2B1, HSPB1, NPM1, DDB1, HMGA1, ZC3HAV1, and HMOX1 was associated with increased relapse-free survival (RFS) in PCa patients. Further, PCa patients with high HSPB1/HMOX1, DDB1/HMOX1, and YWHAZ/HMOX1 showed a worse RFS compared with patients with lower ratios. Moreover, a decrease in RFS for patients with higher scores of this signature was observed using a prognostic risk score model. However, the only factor significantly associated with a higher risk of relapse was high YWHAZ. Multivariable analyses confirmed HSPB1, DDB1, and YWHAZ independence from PCa clinic-pathological parameters. In parallel, co-immunoprecipitation analysis in PCa cells ascertained HO-1/14-3-3ζ/δ (protein encoded by YWHAZ) interaction. Herein, we describe a novel protein interaction between HO-1 and 14-3-3ζ/δ in PCa and highlight these factors as potential therapeutic targets.
Highlights
We have previously identified heme oxygenase 1 (HO-1) molecular partners involved in cell–cell communication and cell adhesion through an integrative “omics” approach [28], establishing four molecular pathways (ANXA2/HMGA1/POU3F1; PLAT/PLAU; TMOD3/RAI14/VWF; NFRSF13/GSN)
In light of the strong anti-tumoral role of HO-1 in Prostate cancer (PCa), we deepened our analyses in the search for other HO-1 interactors with clinical relevance for the disease
We carried out a proteomics analysis, in which PC3 cells, derived from a bone metastasis of PCa [31], were transfected with the HO-1 expression plasmid or with the empty vector as control (Figure 1A)
Summary
Prostate cancer (PCa) is the second most common cancer type in men and the sixth leading cause of cancer-related death in men worldwide [1]. The discovery of new therapeutic avenues in PCa, and the development of effective drugs in the era of personalized medicine, would greatly benefit from the field of proteomics. The proteomics approach for a high-throughput study of biological samples by mass spectrometry has emerged as one of the main analytical strategies from the last years, and proteomic-based studies have greatly improved cancer research. Proteomics represents an important tool for the identification of new molecular targets for PCa’s tailored therapy
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