Prostate epithelial cells possess a uniquely limiting mitochondrial (m-) aconitase activity that minimizes their ability to oxidize citrate. These cells also possess uniquely high cellular and mitochondrial zinc levels. Correlations among zinc, citrate, and m-aconitase in prostate indicated that zinc might be an inhibitor of prostate m-aconitase activity and citrate oxidation. The present studies reveal that zinc at near physiological levels inhibited m-aconitase activity of mitochondrial sonicate preparations obtained from rat ventral prostate epithelial cells. Corresponding studies conducted with mitochondrial sonicates of rat kidney cells revealed that zinc also inhibited the kidney m-aconitase activity. However the inhibitory effect of zinc was more sensitive with the prostate m-aconitase activity. Zinc inhibition fit the competitive inhibitor model. The inhibitory effect of zinc occurred only with citrate as substrate and was specific for the citrate 3 cis-aconitate reaction. Other cations (Ca 2؉ , Mn 2؉ , Cd 2؉) did not result in the inhibitory effects obtained with zinc. The presence of endogenous zinc inhibited the m-aconitase activity of the prostate mitochondrial preparations. Kidney preparations that contain lower endogenous zinc levels exhibited no endogenous inhibition of m-aconitase activity. Studies with pig prostate and seminal vesicle mitochondrial preparations also revealed that zinc was a competitive inhibitor against citrate of m-aconitase activity. The effects of zinc on purified beef heart m-aconitase verified the competitive inhibitor action of zinc. In contrast, zinc had no inhibitory effect on purified cytosolic aconitase. These studies reveal for the first time that zinc is a specific inhibitor of m-aconitase of mammalian cells. In prostate epithelial cells, in situ mitochondrial zinc levels inhibit m-aconitase activity, which provides a mechanism by which citrate oxidation is limited.Prostate secretory epithelial cells have the specialized function and capability of accumulating and secreting extraordinarily high levels of citrate. This is achieved by the existence of a uniquely limiting m-aconitase 1 activity that minimizes the oxidation of citrate via the Krebs cycle. Consequently, citrate synthesized by these cells is accumulated and secreted (which we refer to as "net citrate production"), thereby accounting for the extremely high (20 -150 mM) citrate content of human prostatic fluid. In typical mammalian cell metabolism, m-aconitase is not a regulatory, rate-limiting enzyme. Consequently, the steady-state citrate/isocitrate ratio of most cells is generally maintained at about 11/1, which is established by the aconitase equilibrium reaction, 88 citrate 7 4 cis-aconitate 7 8 isocitrate. In contrast, the citrate/isocitrate ratio in prostate is generally about 30/1. Also, the intracellular citrate concentration of prostate cells is estimated to be about 1.2 mM as compared with about 0.1-0.4 mM for typical mammalian cells. These and other relationships of prostate citrate metabolism an...

The glandular epithelial cells of the human prostate gland have the unique capability and function of accumulating the highest zinc levels of any soft tissue in the body. Zinc accumulation in the prostate is regulated by prolactin and testosterone; however, little information is available concerning the mechanisms associated with zinc accumulation and its regulation in prostate epithelial cells. In the present studies the uptake and accumulation of zinc were determined in the human malignant prostate cell lines LNCaP and PC-3. The results demonstrate that LNCaP cells and PC-3 cells possess the unique capability of accumulating high levels of zinc. Zinc accumulation in both cell types is stimulated by physiological concentrations of prolactin and testosterone. The studies reveal that these cells contain a rapid zinc uptake process indicative of a plasma membrane zinc transporter. Initial kinetic studies demonstrate that the rapid uptake of zinc is effective under physiological conditions that reflect the total and mobile zinc levels in circulation. Correspondingly, genetic studies demonstrate the expression of a ZIP family zinc uptake transporter in both LNCaP and PC-3 cells. The rapid zinc uptake transport process is stimulated by treatment of cells with physiological levels of prolactin and testosterone, which possibly is the result of the regulation of the ZIP-type zinc transporter gene. These zincaccumulating characteristics are specific for prostate cells. The studies support the concept that these prostate cells express a unique hormone-responsive, plasma membrane-associated, rapid zinc uptake transporter gene associated with their unique ability to accumulate high zinc levels.Zinc is an essential component of all cells. It is required for a variety of cellular activities such as metalloenzyme activity, nucleoprotein and nucleic acid structure, and transcription factor interactions. Typically, intracellular zinc is found predominantly (Ͼ 95%) bound to high molecular weight ligands such as metalloenzymes, metalloproteins, nucleoproteins, and nucleic acids. Very little zinc is available as free or loosely bound zinc, which we will refer to as " mobile reactive zinc" (for review, see Refs. 1-3).The prostate gland of humans and other animals is unique in that it accumulates much higher zinc levels than any other soft tissues in the body. For detailed and extensive reviews of zinc-citrate relationships in prostate, see Refs. 4 -6. The special functions associated with the high zinc level of the prostate have not been resolved. The ability of the prostate to accumulate high zinc levels is a function of the glandular secretory epithelial cells. Our recent studies (7) with rat prostate lobes have demonstrated that the epithelial cells contain high levels of intracellular zinc, and, most importantly, contain high levels of mitochondrial zinc. The accumulation of zinc results in the inhibition of mitochondrial aconitase activity which minimizes the ability of these cells to oxidize citrate (8). This is an important r...

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Unlike for most other malignancies, application of FDG PET/CT is limited for renal cell carcinoma (RCC), mainly due to physiological excretion of 18F-fluoro-2-deoxy-2-d-glucose (FDG) from the kidneys, which decreases contrast between renal lesions and normal tissue, and may obscure or mask the lesions of the kidneys. Published clinical observations were discordant regarding the role of FDG PET/CT in diagnosing and staging RCC, and FDG PET/CT is not recommended for this purpose based on current national and international guidelines. However, quantitative FDG PET/CT imaging may facilitate the prediction of the degree of tumor differentiation and allows for prognosis of the disease. FDG PET/CT has potency as an imaging biomarker to provide useful information about patient’s survival. FDG PET/CT can be effectively used for postoperative surveillance and restaging with high sensitivity, specificity, and accuracy, as early diagnosis of recurrent/metastatic disease can drastically affect therapeutic decision and alter outcome of patients. FDG uptake is helpful for differentiating benign or bland emboli from tumor thrombosis in RCC patients. FDG PET/CT also has higher sensitivity and accuracy when compared with bone scan to detect RCC metastasis to the bone. FDG PET/CT can play a strong clinical role in the management of recurrent and metastatic RCC. In monitoring the efficacy of new target therapy such as tyrosine kinase inhibitors (TKIs) treatment for advanced RCC, FDG PET/CT has been increasingly used to assess the therapeutic efficacy, and change in FDG uptake is a strong indicator of biological response to TKI.

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Significant uptake of the thyroid is often identified as an incidental finding on whole-body F18-fluorodeoxyglucose positron emission tomography (FDG-PET) for non-thyroid disease. Sometimes, it is a dilemma for radiologists to interpret clinical significance of thyroid uptake and give adequate recommendation for further evaluation. In general, diffuse uptake of the thyroid glands on FDG-PET is considered to be benign and very likely secondary to thyroiditis and/or hypothyroidism; a further correlation or investigation of the thyroid function and/or ultrasound is helpful. Focal uptake of the thyroid on FDG-PET is defined as an incidentaloma, which is more clinically significant owing to its high risk of malignancy ranging 25-50%. Although maximum standardized uptake value and corresponding computed tomographic finding may help to differentiate benign from malignant lesion, a cytological diagnosis is often advised. The clinical significance of diffuse plus focal uptake of the thyroid on FDG-PET is not well known; it may also be associated with an increased risk of malignancy when compared with a diffuse uptake pattern only.

Diffusely increased uptake is more commonly observed than focal uptake in the spleen on a whole-body [F] fluorodeoxyglucose-positron emission tomography/computed tomography. The significance of diffusely increased splenic uptake varies in different clinical settings. On a pre-therapeutic scan for lymphoma, splenic uptake, greater than hepatic uptake, is a relative reliable indication of lymphomatous involvement of the spleen, unless the patient has a history of recent cytokine administration. In HIV infection, increased splenic uptake is usually noted in the early stage of the disease, which could reflect massive stimulation of B-cells in the spleen by nonreplicating antigenic material. Diffusely increased splenic uptake may also be present in sarcoidosis, malaria, and many inflammatory or hematopoietic diseases. Therapeutic-related reactive splenic uptake concurrent with bone marrow uptake is often secondary to administration of granulocyte colony-stimulating factor for myelosuppression or high-dose interferon-alpha-2b adjuvant therapy for melanoma.

Increased ovarian or endometrial uptake may cause a dilemma in the interpretation of whole body F18-fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging or even misdiagnosis of malignant disease. Knowledge of benign FDG uptake of the ovaries and uterus is important for daily practice of nuclear medicine radiologists. Increased uptake in the ovaries or uterus indicates a pathologic or neoplastic process in postmenopausal patients. In premenopausal women, increased ovarian or endometrial uptake can be functional or malignant. Benign functional uptake of premenopausal ovaries or uterus is related to the menstrual cycle; therefore, information about the patient's menstrual status is crucial for interpretation. In addition, correlation with computed tomography (CT), especially diagnostic CT acquired at the same time of PET/CT is very useful in clarifying the location of the uptake and the existence or disappearance of the discrete lesion. Increased ovarian uptake may also be identified in histologically different benign tumor entities. Nonmenstrual-related endometrial uptake may be present in many benign diseases as well.