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.
|Costello, Leslie C; Franklin, Renty B (2016) Plasma Citrate Homeostasis: How It Is Regulated; And Its Physiological and Clinical Implications. An Important, But Neglected, Relationship in Medicine. HSOA J Hum Endocrinol 1:|
|Costello, Leslie C; Zou, Jing; Franklin, Renty B (2016) In situ clinical evidence that zinc levels are decreased in breast invasive ductal carcinoma. Cancer Causes Control 27:729-35|
|Costello, Leslie C; Franklin, Renty B (2014) The status of zinc in the development of hepatocellular cancer: an important, but neglected, clinically established relationship. Cancer Biol Ther 15:353-60|
|Franklin, Renty B; Zou, Jing; Costello, Leslie C (2014) The cytotoxic role of RREB1, ZIP3 zinc transporter, and zinc in human pancreatic adenocarcinoma. Cancer Biol Ther 15:1431-7|
|Costello, Leslie C; Franklin, Renty B (2013) A Review of the Current Status and Concept of the Emerging Implications of Zinc and Zinc Transporters in the Development of Pancreatic Cancer. Pancreat Disord Ther Suppl 4:|
|Costello, Leslie C; Franklin, Renty B (2013) A review of the important central role of altered citrate metabolism during the process of stem cell differentiation. J Regen Med Tissue Eng 2:|
|Costello, Leslie C; Franklin, Renty B; Reynolds, Mark A et al. (2012) The Important Role of Osteoblasts and Citrate Production in Bone Formation: ""Osteoblast Citration"" as a New Concept for an Old Relationship. Open Bone J 4:|
|Costello, Leslie C; Franklin, Renty B (2012) Cytotoxic/tumor suppressor role of zinc for the treatment of cancer: an enigma and an opportunity. Expert Rev Anticancer Ther 12:121-8|
|Costello, Leslie C; Franklin, Renty B (2011) Integration of molecular genetics and proteomics with cell metabolism: how to proceed; how not to proceed! Gene 486:88-93|
|Costello, Leslie C; Franklin, Renty B (2011) Zinc is decreased in prostate cancer: an established relationship of prostate cancer! J Biol Inorg Chem 16:3-8|
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