Abstract
BackgroundDevelopment of resistance to androgen deprivation therapy (ADT) is a major obstacle for the management of advanced prostate cancer. Therapies with androgen receptor (AR) antagonists and androgen withdrawal initially regress tumors but development of compensatory mechanisms including AR bypass signaling leads to re-growth of tumors. MicroRNAs (miRNAs) are small regulatory RNAs that are involved in maintenance of cell homeostasis but are often altered in tumor cells.ResultsIn this study, we determined the association of genome wide miRNA expression (1113 unique miRNAs) with development of resistance to ADT. We used androgen sensitive prostate cancer cells that progressed to ADT and AR antagonist Casodex (CDX) resistance upon androgen withdrawal and treatment with CDX. Validation of expression of a subset of 100 miRNAs led to identification of 43 miRNAs that are significantly altered during progression of cells to treatment resistance. We also show a correlation of altered expression of 10 proteins targeted by some of these miRNAs in these cells.ConclusionsWe conclude that dynamic alterations in miRNA expression occur early on during androgen deprivation therapy, and androgen receptor blockade. The cumulative effect of these altered miRNA expression profiles is the temporal modulation of multiple signaling pathways promoting survival and acquisition of resistance. These early events are driving the transition to castration resistance and cannot be studied in already developed CRPC cell lines or tissues. Furthermore our results can be used a prognostic marker of cancers with a potential to be resistant to ADT.
Highlights
Development of resistance to androgen deprivation therapy (ADT) is a major obstacle for the management of advanced prostate cancer
MicroRNA expression profile differentiates between untreated LNCaP cells and cells treated with Casodex or subjected to androgen withdrawal: We used genome-wide miRNA array (1113 unique primers) profiling approach to identify specific miRNAs that are involved in development of resistance to Casodex (CDX)
LNCaP-104S cells require DHT for maintaining their androgen dependent (AD) status but when treated with CDX for 3 weeks in CS-FBS, CDX insensitive colonies develop that are independent of androgen (CDXR)
Summary
Development of resistance to androgen deprivation therapy (ADT) is a major obstacle for the management of advanced prostate cancer. Therapies with androgen receptor (AR) antagonists and androgen withdrawal initially regress tumors but development of compensatory mechanisms including AR bypass signaling leads to re-growth of tumors. Because androgen is required for normal growth and functioning of the prostate gland and for development of cancer androgen deprivation therapy (ADT) has become the mainstay for advanced prostate cancer [1]. Noted mechanisms include AR gene amplification, increased coactivator expression, selection of AR gene mutation and sensitivity to growth factors and cytokines [5]. It has been proposed that the increased activity of AR in androgen independent (AI) cells or in relapsed tumors in castrated xenograft mice is mediated through ligand independent mechanism [7] or through promiscuous sensitivity of AR to other steroid hormone, growth factors or cytokines [8]. The exact mechanism of altered gene expression in CRPC is not clear
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