This post was written by Janelle Weaver, Ph.D., a freelance science writer
Prostate cancer is a leading cause of cancer-related death in men in the United States. The development and progression of the disease depend on the actions of male sex hormones called androgens, which bind to the androgen receptor to activate signaling pathways involved in cell growth and survival. Therefore, there is a strong need to identify novel drug targets to alter androgen-receptor signaling and treat this often deadly disease.
As reported on March 26 in Oncotarget, Sanford-Burnham researchers have discovered that a protein called NWD1 affects androgen-receptor signaling to control the growth of prostate cancer cells. “A very limited number of proteins have been shown to specifically and exclusively affect androgen-receptor signaling, so our findings represent a major advance in the field,” said lead study author Ricardo Correa, Ph.D., staff scientist at Sanford-Burnham. “NWD1 could represent a new biomarker for predicting patient prognosis as well as a therapeutic target for a novel class of prostate cancer drugs.”
High levels of androgens are critical for the growth of prostate cancer cells in early disease stages, and one major type of therapy focuses on inhibiting androgens. But over time, prostate cancer cells often respond to hormone therapy by expressing high levels of the androgen receptor, allowing these castration-resistant cells to grow even when androgen levels are low. Castration-resistant prostate cancer is an advanced form of the disease associated with poor survival rates. However, both early and advanced stages of prostate cancer depend on androgen-receptor signaling, highlighting the value of targeting this pathway for treating a broad range of patients.
While searching for novel modulators of androgen-receptor signaling, Correa and his team became interested in the nucleotide-binding domain and leucine-rich repeat (NLR) family of proteins. These proteins are involved in recognizing pathogens and cell-injury signals and activating immune-defense pathways, but they have also been implicated in a variety of cancers. In particular, the researchers were intrigued by an NLR-related protein called NWD1, which was previously identified in zebrafish but had not yet been analyzed in humans.
In the new study, Correa and his colleagues found that the expression of the human NWD1 gene was very high in prostate tissue and other parts of the male reproductive system. Moreover, NWD1 expression was higher than normal in human prostate cancer cell lines, especially in castration-resistant and highly metastatic cell lines. Similarly, NWD1 protein levels were higher than normal in advanced-stage and castration-resistant prostate tumor tissue from patients.
Taken together, the findings suggest that NWD1 could be a potential prostate cancer biomarker because high levels of the protein are associated with malignant progression. “We believe that NWD1 could represent a promising biomarker because changes in NWD1 expression happen at stages where the levels of prostate-specific antigen (PSA), a protein that is widely used to screen men for prostate cancer, are not very accurate in the clinic,” Correa said.
In addition to its potential use for predicting patient prognosis, NWD1 could represent a promising therapeutic target. When the researchers inhibited the activity of the NWD1 gene in prostate cancer cells, they noticed a drop in androgen-receptor levels as well as a decrease in cell growth and survival. On the other hand, an increase in NWD1 activity led to a rise in androgen-receptor levels in these cells.
Their experiments also shed light on the molecular mechanisms by which NWD1 affects androgen-receptor signaling. NWD1 silencing fed the activity of cancer-related genes such as PDEF (prostate-derived epithelial factor), which is known to bind to androgen receptors and belongs to a family of proteins that regulate cell growth and survival. Moreover, a protein called sex-determining region Y (SRY), which controls sex determination during fetal development, affected the activity of the NWD1 gene. Thus, the findings not only reveal a novel molecular pathway involved in prostate cancer, but also suggest that drugs targeting NWD1 could eventually become a new class of treatments for the disease.
“It is well known that mechanisms driving the higher stability of androgen-receptor protein levels are responsible for the hormone-independent progression of prostate cancer, which is very challenging to treat and is associated with a poor prognosis,” Correa said. “Because NWD1 plays an important role in stabilizing androgen-receptor protein levels, we believe that the design of NWD1 inhibitors could have a fruitful therapeutic impact on controlling androgen-receptor activity and possibly preventing disease progression.”