Abstract
Gastrin-releasing peptide receptor (GRPR) is known to be overexpressed in several human malignancies, including prostate cancer, and has been implicated in multiple important neoplastic signaling pathways. We recently have shown that GRPR is an ERG and ETV1 target gene in prostate cancer, using a genome-wide scale and exon-level expression microarray platform. Due to its cellular localization, the relevance of its function and the availability of blocking agents, GRPR seems to be a promising candidate as therapeutic target. Our present work shows that effective knockdown of GRPR in LNCaP and VCaP cells attenuates their malignant phenotype by decreasing proliferation, invasion and anchorage-independent growth, while increasing apoptosis. Using an antibody microarray we were able to validate known and identify new targets of GRPR pathway, namely AKT1, PKCε, TYK2 and MST1. Finally, we show that overexpression of these GRPR targets is restricted to prostate carcinomas harboring ERG and/or ETV1 rearrangements, establishing their potential as therapeutic targets for these particular molecular subsets of the disease.
Highlights
Prostate carcinoma (PCa) is the most incident neoplasia in men and the second leading cancer-related cause of death [1]
Upon successful and stable Gastrin-releasing peptide receptor (GRPR) silencing in both cell lines, we observed a decline of malignant cells’ phenotype through reduction of cell proliferation, invasion and ability to growth in the absence of cell attachment, and by an increment of apoptosis
GRPR and its specific peptide have been associated with an oncogenic role in different tissues and models, the present work is the first report ascertaining the malignant impact of this receptor in prostate carcinogenesis
Summary
Prostate carcinoma (PCa) is the most incident neoplasia in men and the second leading cancer-related cause of death [1]. PCa is a heterogeneous disease and current therapeutic strategies are dependent on TNM staging, Gleason scoring, PSA levels and overall health status. Primary treatment consists mainly of radical prostatectomy and/or radiation therapy, which may be supplemented with androgen ablation [2]. Many patients are identified with locally, surgically curable, disease, there is a subset of patients that progress or show metastatic prostate cancer, where the gold standard therapy is androgen ablation. Recurrence is frequent, and many patients develop metastatic disease, for which chemotherapy is only moderately effective [3]. Novel therapeutic approaches to metastatic prostate cancer are needed
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