Mitochondrial aconitase and citrate metabolism in malignant and nonmalignant human prostate tissues.
Mitochondrial aconitase and citrate metabolism in malignant and nonmalignant human prostate tissues.
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恶性和非恶性人类前列腺组织中的线粒体顺乌头酸酶和柠檬酸代谢。
DOI：
10.1186/1476-4598-5-14
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发表时间：
2006-04-04
期刊：
影响因子：
37.3
通讯作者：
Costello, Leslie C.
中科院分区：
文献类型：
--
作者：
Singh, Keshav K.;Desouki, Mohamed M.;Franklin, Renty B.;Costello, Leslie C.
在前列腺癌中，正常的产生柠檬酸盐的腺分泌上皮细胞经历代谢转化为恶性柠檬酸盐氧化细胞。m-柠檬酸酶是参与这种改变的柠檬酸盐代谢的关键步骤，而柠檬酸盐代谢是前列腺恶性肿瘤所必需的。前列腺上皮细胞中的限制性间乌头酸酶活性可能是间乌头酸酶水平降低和/或抑制现有间乌头酸酶的结果。早期的研究发现锌是前列腺细胞中间乌头酸酶活性的抑制剂，并且恶性细胞中锌的耗尽是这种代谢转化的重要因素。然而，一种可能性仍然存在，即改变的表达和水平的m-乌头酸酶也可能参与这种代谢转化。为了解决这个问题，原位水平的m-乌头酸酶的前列腺癌组织切片和恶性前列腺细胞系的免疫组织化学分析确定。免疫细胞化学程序成功地确定了存在的m-乌头酸酶定位在PC-3，LNCaP，和DU-145恶性前列腺细胞系的线粒体隔室。前列腺癌受试者的前列腺组织切片的检查表明，m-乌头酸酶存在于正常腺体、增生腺体、腺瘤性腺体和前列腺上皮内肿瘤病灶的腺上皮中。对产柠檬酸腺瘤腺体与氧化柠檬酸腺癌腺体的腺上皮中m-乌头酸酶的相对水平进行定量分析，发现m-乌头酸酶水平无显著差异。这与存在于相同组织样品中的恶性腺体相对于增生腺体中ZIP 1锌转运蛋白的下调形成对比。结果表明，在产生柠檬酸的腺上皮细胞中存在间乌头酸酶;因此，缺乏间乌头酸酶与阻止这些细胞中柠檬酸氧化的限制间乌头酸酶活性无关。恶性细胞中的间乌头酸酶水平得以维持，因此酶水平的改变与间乌头酸酶活性的增加无关。因此，抑制间乌头酸酶的锌水平升高是导致正常和增生性前列腺上皮细胞中柠檬酸盐氧化受损的原因。此外，ZIP 1锌转运蛋白的下调和相应的锌消耗导致恶性前列腺细胞中现有的间乌头酸酶活性的增加。这些研究现在定义了代谢转化的机制，该机制表征了正常柠檬酸盐产生上皮细胞向恶性柠檬酸盐氧化细胞的基本转变。
In prostate cancer, normal citrate-producing glandular secretory epithelial cells undergo a metabolic transformation to malignant citrate-oxidizing cells. m-Aconitase is the critical step involved in this altered citrate metabolism that is essential to prostate malignancy. The limiting m-aconitase activity in prostate epithelial cells could be the result of a decreased level of m-aconitase enzyme and/or the inhibition of existing m-aconitase. Earlier studies identified zinc as an inhibitor of m-aconitase activity in prostate cells; and that the depletion of zinc in malignant cells is an important factor in this metabolic transformation. However, a possibility remains that an altered expression and level of m-aconitase enzyme might also be involved in this metabolic transformation. To address this issue, the in situ level of m-aconitase enzyme was determined by immunohistochemical analysis of prostate cancer tissue sections and malignant prostate cell lines. The immunocytochemical procedure successfully identified the presence of m-aconitase localized in the mitochondrial compartment in PC-3, LNCaP, and DU-145 malignant prostate cell lines. The examination of prostate tissue sections from prostate cancer subjects demonstrated that m-aconitase enzyme is present in the glandular epithelium of normal glands, hyperplastic glands, adenocrcinomatous glands, and prostatic intraepithelial neoplastic foci. Quantitative analysis of the relative level of m-aconitase in the glandular epithelium of citrate-producing adenomatous glands versus the citrate-oxidizing adenocarcinomatous glands revealed no significant difference in m-aconitase enzyme levels. This is in contrast to the down-regulation of ZIP1 zinc transporter in the malignant glands versus hyperplastic glands that exists in the same tissue samples. The results demonstrate the existence of m-aconitase enzyme in the citrate-producing glandular epithelial cells; so that deficient m-aconitase enzyme is not associated with the limiting m-aconitase activity that prevents citrate oxidation in these cells. The level of m-aconitase is maintained in the malignant cells; so that an altered enzyme level is not associated with the increased m-aconitase activity. Consequently, the elevated zinc level that inhibits m-aconitase enzyme is responsible for the impaired citrate oxidation in normal and hyperplastic prostate glandular epithelial cells. Moreover, the down-regulation of ZIP1 zinc transporter and corresponding depletion of zinc results in the increase in the activity of the existing m-aconitase activity in the malignant prostate cells. The studies now define the mechanism for the metabolic transformation that characterizes the essential transition of normal citrate-producing epithelial cells to malignant citrate-oxidizing cells.
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恶性和非恶性人类前列腺组织中的线粒体顺乌头酸酶和柠檬酸代谢。
影响因子：
37.3
作者：
Singh, Keshav K.;Desouki, Mohamed M.;Franklin, Renty B.;Costello, Leslie C.
通讯作者：
Costello, Leslie C.
影响因子：
2.1
作者：
Costello, LC;Liu, Y;Franklin, RB
通讯作者：
Franklin, RB
影响因子：
11.5
作者：
Desouki, MM;Rowan, BG
通讯作者：
Rowan, BG
影响因子：
4.1
作者：
COSTELLO, LC;LIU, YY;FRANKLIN, RB
通讯作者：
FRANKLIN, RB
影响因子：
3.9
作者：
Costello, LC;Franklin, RB;Kennedy, MC
通讯作者：
Kennedy, MC