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Abstract
BackgroundThe androgen receptor is a ligand-induced transcriptional factor, which plays an important role in normal development of the prostate as well as in the progression of prostate cancer to a hormone refractory state. We previously reported the identification of a novel AR coactivator protein, L-dopa decarboxylase (DDC), which can act at the cytoplasmic level to enhance AR activity. We have also shown that DDC is a neuroendocrine (NE) marker of prostate cancer and that its expression is increased after hormone-ablation therapy and progression to androgen independence. In the present study, we generated tetracycline-inducible LNCaP-DDC prostate cancer stable cells to identify DDC downstream target genes by oligonucleotide microarray analysis.ResultsComparison of induced DDC overexpressing cells versus non-induced control cell lines revealed a number of changes in the expression of androgen-regulated transcripts encoding proteins with a variety of molecular functions, including signal transduction, binding and catalytic activities. There were a total of 35 differentially expressed genes, 25 up-regulated and 10 down-regulated, in the DDC overexpressing cell line. In particular, we found a well-known androgen induced gene, TMEPAI, which wasup-regulated in DDC overexpressing cells, supporting its known co-activation function. In addition, DDC also further augmented the transcriptional repression function of AR for a subset of androgen-repressed genes. Changes in cellular gene transcription detected by microarray analysis were confirmed for selected genes by quantitative real-time RT-PCR.ConclusionTaken together, our results provide evidence for linking DDC action with AR signaling, which may be important for orchestrating molecular changes responsible for prostate cancer progression.
Highlights
The androgen receptor is a ligand-induced transcriptional factor, which plays an important role in normal development of the prostate as well as in the progression of prostate cancer to a hormone refractory state
The change in gene expression of androgen-regulated genes caused by sustained dopa decarboxylase (DDC) overexpression were analyzed in vitro by the generation of LNCaP cells stably expressing doxycycline hyclate (Dox)-inducible DDC
No detectable DDC protein was found under the Dox-induced (+Dox) or mock-induced (-Dox) condition in the LNCaP-pDEST cell line, confirming the fact that endogenous DDC protein expression levels in this cell line are below detection when directly compared to ectopic overexpression (Figure 1A) [18]
Summary
The androgen receptor is a ligand-induced transcriptional factor, which plays an important role in normal development of the prostate as well as in the progression of prostate cancer to a hormone refractory state. We have shown that DDC is a neuroendocrine (NE) marker of prostate cancer and that its expression is increased after hormone-ablation therapy and progression to androgen independence. In most cases prostate cancer begins as an androgen-dependent tumor that undergoes clinical regression in response to pharmacological and surgical strategies that reduce testosterone concentration. This form of therapy is generally used to treat advanced cancer or those that recur after radiation or surgical procedures to remove the primary cancer. Despite androgen withdrawal therapy most patients develop lethal androgen-independent (AI) tumors [2,3]. The underlying molecular mechanism involved in androgen-independent prostate cancer and the therapies aimed at this are the active areas of current research
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