Prostate cancer (PCa) is the second leading cause of cancer deaths in males and combined with benign prostatic hyperplasia (BPH) represents the leading neoplastic disease in men. It is now evident that altered intermediary metabolism is a major factor in the pathogenesis of PCa and BPH. Prostate secretory epithelial cells accumulate uniquely high levels of aspartate which is required for their unique function of accumulating and secreting extraordinarily high levels of citrate. Unlike virtually all other mammalian cells, aspartate is an essential amino acid in prostate cells. To achieve this capability, prostate cells contain a unique high-affinity aspartate transport mechanism that facilitates the uptake of aspartate from blood against a large concentration gradient in order to maintain the high level of cellular aspartate. Evidence supports the concept that the transport activity is due to the existence of a unique operational aspartate transporter that is regulated by testosterone and prolactin. Virtually all genetically identified glutamate-aspartate transporters that have been genetically identified in mammalian operate glutamate, not aspartate transporters. Therefore, the relationship of the high-affinity aspartate transporter to a genetically identifiable transporter becomes a key issue. The broad objectives are to elucidate the mechanisms associated with unique metabolic capabilities of prostate cells; to establish the relation of altered metabolism in neoplastic prostate cells; and to employ this information in new approaches to the diagnosis and treatment of PCa and/or BPH.
The specific aims of this application are: to establish the kinetic characteristics of the aspartate transporter; to establish the mechanism of hormonal regulation of the transporter; to determine the genetic regulation of the transporter; and to establish the expression and functional operation of the transporter in prostate versus non-prostate cells. Kinetic and genetic studies will be conducted with freshly prepared rat ventral prostate cells that provides an excellent model for the transport mechanism. Comparative studies of the expression and functioning of the aspartate transporter will involve human prostate cell lines and non-prostate cells. The studies should reveal that prostate secretory epithelial cells uniquely express a functional aspartate transporter that is not associated with other mammalian cells; and/or that unique cellular environmental conditions of prostate cells are responsible for the operation of the transporter as a high-affinity aspartate transporter.
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