Abstract
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.
Highlights
Prostate cancer (PCa) is the most prevalent type of cancer among men in the United States and accounts for roughly 10% of cancer-specific mortality [1]
Given the association of NCL-dependent miRNAs with cancer, and that NCL expression increases in malignant cells where it is aberrantly expressed on the cell surface, we developed a therapeutic anticancer agent to bind NCL and block its miRNA biogenesis activity
We have previously shown that 4LB5 gets internalized into breast cancer cells causing reduction three lines at 48 h after treatment were decreased by 30–60% compared to controls (Figure 2C)
Summary
Prostate cancer (PCa) is the most prevalent type of cancer among men in the United States and accounts for roughly 10% of cancer-specific mortality [1]. Advanced stage PCa is initially treated effectively with androgen deprivation therapy (ADT), progression to castration-resistant prostate cancer (CRPC) usually develops about 1 year after initiation of ADT [2]. CRPC is becoming increasingly prevalent, with an average of 2–4% of PCa cases progressing to CRPC each year [3]. To achieve a CRPC phenotype, PCa cells evade ADT by acquiring aberrations in the androgen receptor (AR) pathway [4,5]. More than 70% of metastatic CRPC cases exhibit at least one AR pathway aberration [6], with over 50% of these tumors harboring a mutated or amplified AR gene [7]
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