PCA is the most diagnosed cancer in men, and is the second leading cause of male cancer deaths in the USA (1). PCA is multifocal, and the cancerous gland contains multiple independent tumors, demonstrating disease heterogeneity (2). A unique PCA characteristic is its initial dependence on As for growth. As a result, standard strategies for PCA treatment rely on blockade of A action by: 1. Decreasing circulating A levels via chemical or physical castration; or 2. Treatment with As (i.e., DHT) that compete for binding to the AR (3,4). The major limitation of this approach, however, is that the PCA frequently develops into A-independent (AI) lesions, characterized by recurrent growth and metastasis even in the continued presence of the hormonal therapies. To date, there is no cure for AI PCA (5).
Mechanisms involved in the transition of PCA from A-dependent (AD) to AI remain poorly defined, although recent findings suggest a role for AR (6). First, AR is overexpressed in up to one third of AI PCAs, suggesting a compensatory mechanism by which the AR adjusts its physiologic rheostat to respond to lower serum levels ofAs (3,7). Second, AI lesions exhibit frequent AR mutations, which may allow for its activation by other As or even anti-As (6). Third, AR can be activated by growth factors other than As (8). In all cases, activated AR promotes cell growth and inhibits cell death by regulating expression of specific genes.
In addition to becoming active by binding As, new evidence suggests AR can support transcription in response to growth factor stimulation. For example, in DU145 cells ectopically expressing human AR, stimulation ofendogenous insulinlike growth factor 1 (IGF-1) receptors activates transcription ofA response element (ARE)-regulated reporter genes (9). Similarly, in LNCaP cells, IGF-1 can stimulate secretion of ARE-regulated prostate specific antigen (PSA) in absence of As (10). Overexpression of the receptor tyrosine kinase (RTK) HER2/neu (11), as well as treatment with forskolin ( 12,13) induces PSA expression. Mechanisms involved in the growth factor-regulated activation of AR are not fully understood. Herein, we show that stimulation of LNCaP cells with reagents that increase levels of intracellular 3',5'-cAMP induces protein kinase A (PKA)-dependent activation of AR. Importantly, we show that inhibition of PKA activity abrogates the DHT-mediated activation of AR. We also provide evidence that stimulation of the LNCaP cells with epidermal growth factor (EGF) does not support AR activation.
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