NCL Inhibition Exerts Antineoplastic Effects against Prostate Cancer Cells by Modulating Oncogenic MicroRNAs

Abstract

<jats:p>Prostate cancer (PCa) is the most frequently diagnosed cancer in men and second most common cause of cancer-related deaths in the United States. Androgen deprivation therapy (ADT) is only temporarily effective for advanced-stage PCa, as the disease inevitably progresses to castration-resistant prostate cancer (CRPC). The protein nucleolin (NCL) is overexpressed in several types of human tumors where it is also mislocalized to the cell surface. We previously reported the identification of a single-chain fragment variable (scFv) immuno-agent that is able to bind NCL on the surface of breast cancer cells and inhibit proliferation both in vitro and in vivo. In the present study, we evaluated whether NCL could be a valid therapeutic target for PCa, utilizing DU145, PC3 (CRPC), and LNCaP (androgen-sensitive) cell lines. First, we interrogated the publicly available databases and noted that higher NCL mRNA levels are associated with higher Gleason Scores as well as with recurrent and metastatic tumors. Then, using our anti-NCL scFv, we demonstrated that NCL is expressed on the surface of all three tested cell lines and that NCL inhibition results in reduced proliferation and migration. We also measured the inhibitory effect of NCL targeting on the biogenesis of oncogenic microRNAs such as miR-21, -221 and -222, which was cell context dependent. Taken together, our data provide evidence that NCL targeting inhibits the key hallmarks of malignancy in PCa cells and may provide a novel therapeutic option for patients with advanced-stage PCa.</jats:p>

Overexpression of Nucleolin and Associated Genes in Prostate Cancer

“…Sheetz et al investigated NCL expression in tumor tissues using the available database TCGA. In this study, increased NCL mRNA expression was associated with Gleason scores (8-10 > to 6-7), and with biochemical recurrence and metastases [29]. This result was confirmed using the TCGA cohort.…”

“…In PCa, the majority of studies on NCL investigate the anti-tumor activities of targeting molecules or decipher their mechanisms of action using in vitro models. Recently, NCL inhibition by a single-chain fragment-variable (scFv, 4LB5) resulted in the reduced proliferation and migration of tumor prostate DU145 and PC3 cells [29]. As for the 4LB5 scFv, the aptamer AS1411 and its formulated nanoparticles, the pleiotrophin P11-136 peptide and the multivalent pseudopeptides NucAnts, have demonstrated a growth inhibition of PCa cells [30][31][32][33][34][35][36][37].…”

Limb expression 1‐like protein promotes epithelial–mesenchymal transition and epidermal growth factor receptor‐tyrosine kinase inhibitor resistance via nucleolin‐mediated ribosomal RNA synthesis in non‐small cell lung cancer

“…Nucleolin (NCL) is an RNA‐binding protein that participates in DNA transcription, ribosomal biogenesis, and post‐transcriptional regulation 44,45,49,50 . It physically associates with miRNAs, lncRNAs, and mRNAs and regulates the modification and metabolism of these molecules to control specific gene expression 51,52 . The expression of NCL is increased in highly proliferating cells, and higher NCL level correlates with more growth and metastasis of tumors 51,53,54 .…”

Cancer Stem Cells and Nucleolin as Drivers of Carcinogenesis

“…Nucleolin also regulates the expression of microRNAs (miRNAs) namely miR-21, miR-221, miR-222 and miR-103, whose overexpression is associated with breast cancer initiation, metastases and therapy resistance [ 156 ]. Similarly, in prostate cancer cell lines, targeting and inhibition of nucleolin promoted a decrease in the level of those same oncogenic microRNAs and impaired cell proliferation and migration [ 157 ].…”