Targeting aspartate aminotransferase in breast cancer.
Targeting aspartate aminotransferase in breast cancer.
复制标题
DOI：
10.1186/bcr2154
复制
发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Chesney J
中科院分区：
文献类型：
--
作者：
Thornburg JM;Nelson KK;Clem BF;Lane AN;Arumugam S;Simmons A;Eaton JW;Telang S;Chesney J
乳腺癌细胞中糖酵解相对于邻近的正常细胞增加，以产生生存、生长和侵袭所需的ATP和合成代谢前体。糖酵解也是还原型细胞质烟酰胺腺嘌呤二核苷酸（NADH）的关键来源，这是电子穿梭进入线粒体进行电子传递所必需的。乳酸脱氢酶（LDH）通过将丙酮酸转化为乳酸来调节糖酵解通量，并已发现在乳腺肿瘤中高度表达。天冬氨酸氨基转移酶（AAT）与苹果酸脱氢酶协同作用，将电子从NADH转移到线粒体内膜。草酸盐是LDH和AAT的抑制剂，我们假设草酸盐可能会破坏乳腺癌细胞的代谢和生长。我们研究了草氨酸和AAT抑制剂氨基氧乙酸（AOA）对MDA-MB-231细胞中13 C-葡萄糖利用、氧消耗、NADH和ATP的影响。然后，我们确定了草酸和AOA对正常人乳腺上皮细胞和MDA-MB-231乳腺癌细胞增殖的影响，以及对无胸腺BALB/c雌性小鼠中作为肿瘤的MDA-MB-231细胞生长的影响。我们在MDA-MB-231细胞中异位表达AAT，并检查了对oxamate的细胞抑制作用的后果。最后，我们检测了AAT特异性siRNA转染对MDA-MB-231细胞增殖的影响。我们发现草胺酸盐并没有像其LDH抑制活性所预测的那样减少细胞乳酸的产生，但确实具有与AOA抑制AAT类似的抗代谢作用。具体来说，我们发现，草氨酸和AOA减少了13 C-葡萄糖衍生的碳流入谷氨酸和尿苷，这两种产品的线粒体三羧酸循环，以及氧消耗，电子传递链活性的措施。草酸盐和AOA还选择性抑制MDA-MB-231细胞相对于正常人乳腺上皮细胞的增殖，并减少无胸腺小鼠中MDA-MB-231乳腺肿瘤的生长。重要的是，我们发现AAT在MDA-MB-231细胞中的异位表达赋予了对草氨酸盐的抗增殖作用的抗性，并且AAT的siRNA沉默降低了MDA-MB-231细胞增殖。我们的结论是，AAT可能是一个有效的分子靶点的发展抗肿瘤药物。
Glycolysis is increased in breast adenocarcinoma cells relative to adjacent normal cells in order to produce the ATP and anabolic precursors required for survival, growth and invasion. Glycolysis also serves as a key source of the reduced form of cytoplasmic nicotinamide adenine dinucleotide (NADH) necessary for the shuttling of electrons into mitochondria for electron transport. Lactate dehydrogenase (LDH) regulates glycolytic flux by converting pyruvate to lactate and has been found to be highly expressed in breast tumours. Aspartate aminotransferase (AAT) functions in tandem with malate dehydrogenase to transfer electrons from NADH across the inner mitochondrial membrane. Oxamate is an inhibitor of both LDH and AAT, and we hypothesised that oxamate may disrupt the metabolism and growth of breast adenocarcinoma cells. We examined the effects of oxamate and the AAT inhibitor amino oxyacetate (AOA) on 13C-glucose utilisation, oxygen consumption, NADH and ATP in MDA-MB-231 cells. We then determined the effects of oxamate and AOA on normal human mammary epithelial cells and MDA-MB-231 breast adenocarcinoma cell proliferation, and on the growth of MDA-MB-231 cells as tumours in athymic BALB/c female mice. We ectopically expressed AAT in MDA-MB-231 cells and examined the consequences on the cytostatic effects of oxamate. Finally, we examined the effect of AAT-specific siRNA transfection on MDA-MB-231 cell proliferation. We found that oxamate did not attenuate cellular lactate production as predicted by its LDH inhibitory activity, but did have an anti-metabolic effect that was similar to AAT inhibition with AOA. Specifically, we found that oxamate and AOA decreased the flux of 13C-glucose-derived carbons into glutamate and uridine, both products of the mitochondrial tricarboxylic acid cycle, as well as oxygen consumption, a measure of electron transport chain activity. Oxamate and AOA also selectively suppressed the proliferation of MDA-MB-231 cells relative to normal human mammary epithelial cells and decreased the growth of MDA-MB-231 breast tumours in athymic mice. Importantly, we found that ectopic expression of AAT in MDA-MB-231 cells conferred resistance to the anti-proliferative effects of oxamate and that siRNA silencing of AAT decreased MDA-MB-231 cell proliferation. We conclude that AAT may be a valid molecular target for the development of anti-neoplastic agents.
登录
查看更多内容
影响因子：
5.6
作者：
BORISOV, VV;BORISOVA, SN;BRAUNSTEIN, AE
通讯作者：
BRAUNSTEIN, AE
DOI：
10.1073/pnas.77.5.2559
发表时间：
1980-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
FORD, GC;EICHELE, G;JANSONIUS, JN
通讯作者：
JANSONIUS, JN
DOI：
10.1186/bcr813
发表时间：
2004
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Bos R;van Diest PJ;van der Groep P;Shvarts A;Greijer AE;van der Wall E
通讯作者：
van der Wall E
影响因子：
8.8
作者：
Deming SL;Nass SJ;Dickson RB;Trock BJ
通讯作者：
Trock BJ
影响因子：
2.7
作者：
KAMITORI, S;OKAMOTO, A;KATSUBE, Y
通讯作者：
KATSUBE, Y