Receptor Tyrosine Kinase‐like Orphan Receptor 1 (ROR1) as a Selective Molecular Target in Androgen‐Dependent and Androgen‐Independent Prostate Cancer

Abstract

Prostate cancer is a disease that has a high prevalence and mortality amongst men. The severity of the cancer is stratified by risk, which is based on the Gleason grade, prostate‐specific antigen (PSA) level, and clinical staging. Unlike breast cancer which can be classified into subtypes based on molecular heterogeneity, prostate cancer has no such classification and is therefore treated with non‐specific chemotherapy and radiation if local, and androgen deprivation therapy (ADT) if metastatic. It is of the utmost importance to investigate molecular targets that can specifically eradicate prostate cancer while retaining the functions of normal tissue. Receptor tyrosine kinase‐like orphan receptor 1 (ROR1) is a receptor that is highly expressed in embryogenesis and cancer, while being minimally expressed in normal tissue. In particular, prostate cancer exhibits moderate to high levels of ROR1 expression. The goal of this study is to elucidate the role of ROR1 in aggressive prostate cancer and selectively target it for treatment. Our laboratory had previously characterized Strictinin, a ROR1 inhibitor, as being selectively cytotoxic against TNBC via inhibition of the ROR1 receptor. We hypothesize that Strictinin can reduce the proliferation and invasion of prostate cancer and may potentially serve as a specific therapeutic agent. Preliminary results indicate that Strictinin is selectively lethal to androgen‐dependent and androgen‐independent prostate cancer cell lines. Strictinin treatment reduced expression of proteins downstream of ROR1 implicated in promoting migration, invasion, and anti‐apoptosis. Furthermore, Strictinin treatment decreased migration and invasion while inducing apoptosis in PC3 and LnCAP cell lines, providing evidence that inhibition of the ROR1 molecular pathway is linked to reduction of cancerous phenotypes. These preliminary results indicate that ROR1 could be a novel molecular target that can be utilized for subtyping and treating prostate cancer. The data from this study will establish Strictinin as a potential therapeutic that targets ROR1 to reduce migration, invasion, and survival of prostate cancer.

Receptor tyrosine kinase-like orphan receptor 1 inhibitor strictinin exhibits anti-cancer properties against highly aggressive androgen-independent prostate cancer

“…ROR1 can promote the migration and invasion of cancer [29,35,36]. Therefore, we predicted that strictinin should suppress the migration and invasion of prostate cancer cells (Figures 4 and 5).…”

“…Our lab has previously shown that strictinin can selectively inhibit ROR1 in triple-negative breast cancer (TNBC) [29]. Corroborating these results was a reduction in oncogenic signaling pathways as well as migration, invasion, and anti-apoptosis in aggressive TNBC cells [29]. Furthermore, our previous research identified that ROR1 was an important molecular marker for AR neg -AI prostate cancer cell lines (PC3 and DU145) [30].…”

“…AKT and GSK3β are often phosphorylated in dysregulated cancer signaling that arises from aberrant RTK activity [34]. Prior research in our lab identified a strong interaction between ROR1 and strictinin through in silico docking analysis and isothermal calorimetry experiments [29]. Since our prior studies suggested that strictinin interacts with ROR1 and that ROR1 expression was most upregulated in PC3 cells, we sought to explore whether strictinin suppresses ROR1 and downstream cancerous signaling in PC3 cells.…”

“…One such natural compound, known as strictinin, has medicinal properties for a variety of ailments [26][27][28][29]. Our lab has previously shown that strictinin can selectively inhibit ROR1 in triple-negative breast cancer (TNBC) [29]. Corroborating these results was a reduction in oncogenic signaling pathways as well as migration, invasion, and anti-apoptosis in aggressive TNBC cells [29].…”

“…One potential untapped resource of small molecule inhibitors can be obtained through extraction from medicinal plants and teas. One such natural compound, known as strictinin, has medicinal properties for a variety of ailments [26][27][28][29]. Our lab has previously shown that strictinin can selectively inhibit ROR1 in triple-negative breast cancer (TNBC) [29].…”