Small molecule unlocks key prostate cancer survival tactic
The most recent in a series of studies from a team at the UC Davis Comprehensive Cancer Center has shown that a single molecule is at the heart of one of the most basic survival tactics of prostate cancer cells.
A paper published today by the Public Library of Science identifies a microRNA called miR-125b as a potential target for treatments designed to stop the proliferation of prostate cancer cells, particularly in patients who have developed a late-stage form of the disease resistant to androgen deprivation therapy.
MicroRNAs are small, single strands of RNA that regulate gene expression processes between larger strands of RNA — that is, they play vital roles in turning genes on and off. RNA, or ribonucleic acid, is a family of large molecules involved in the coding, decoding, regulation and expression of genes.
The team, led by UC Davis urology professor Ralph de Vere White, director of the comprehensive cancer center and senior author on the study, had found in previous studies over the last several years that miR-125b is highly expressed in human prostate cancer, turning off some tumor genes that if left unaltered would have made therapy more effective. This was particularly true at the point in late-stage treatment when patients’ levels of testosterone, or androgen, have purposely been lowered as a form of treatment for metastatic prostate cancer. Testosterone is a driver of tumor growth.
“Our latest research demonstrates that elevated MiR-125B in prostate cancer cells is a mechanism that thwarts our efforts to eradicate the disease,” said de Vere White.
The UC Davis study details exactly how miR-125b represses a protein called p14ARF in two prostate cancer cell lines and in a mouse model. The study is important because it is the first to identify miR-125b as a direct regulator of p14ARF in metastatic prostate cancer cells.
P14ARF is an important link in the pathway between two genes that suppress prostate cancer cells, p53 and PUMA. When miR-125b downregulates p14ARF, p53 is restrained from its job of killing cancer cells. Treatment of prostate cancer cells with an inhibitor of miR-125 results in increased expression of p14ARF and full functioning of p53, leading to the death of prostate cancer cells, known as apoptosis, and a concomitant slowing tumor growth.
This is known as a p53-dependent pathway; there’s also a p53-independent pathway, and miR125b downregulates that as well. Thus this paper shows that, through its manipulation of p14ARF, miR-125b is a major modulator of cell death, whether p53-dependent or independent. Since all prostate cancer cells are one or the other, this phenomenon impacts all of them, which makes miR-125b an important molecule in the progression of prostate cancer.
“These latest findings reinforce our belief that miR-125b has potential as a therapeutic target for the management of patients with metastatic prostate cancer,” said deVere White. “We’re pleased that these data build so successfully on our earlier studies of miR-125b and bring us closer to patient treatment.”
Other authors were Sumaira Amir, Ai-Hong Ma, Xu-Bao Shi, Lingru Xue, Hsing-Jien Kung, all of the UC Davis School of Medicine. The study was supported by grants from the National Cancer Institute (CA136597) and Department of Defense (PC080488).
UC Davis Comprehensive Cancer Center is the only National Cancer Institute-designated center serving the Central Valley and inland Northern California, a region of more than 6 million people. Its specialists provide compassionate, comprehensive care for more than 9,000 adults and children every year, and access to more than 150 clinical trials at any given time. Its innovative research program engages more than 280 scientists at UC Davis, Lawrence Livermore National Laboratory and Jackson Laboratory (JAX West), whose scientific partnerships advance discovery of new tools to diagnose and treat cancer. Through the Cancer Care Network, UC Davis collaborates with a number of hospitals and clinical centers throughout the Central Valley and Northern California regions to offer the latest cancer care. Its community-based outreach and education programs address disparities in cancer outcomes across diverse populations. For more information, visit cancer.ucdavis.edu.