AMP-activated protein kinase activators can inhibit the growth of prostate cancer cells by multiple mechanisms
AMP-activated protein kinase activators can inhibit the growth of prostate cancer cells by multiple mechanisms
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DOI：
10.1016/j.bbrc.2004.06.133
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发表时间：
2004-08-11
影响因子：
3.1
通讯作者：
Luo, ZJ
中科院分区：
文献类型：
--
作者：
Xiang, XQ;Saha, AK;Luo, ZJ
前列腺癌细胞的快速生长需要高速率的脂肪酸合成和蛋白质合成。我们在这里报道，这些细胞的生长被amp激活的蛋白激酶（AMPK）的激活剂孵育明显减少，AMPK是一种燃料感应酶，已被证明在完整组织中减少这两个过程。当AMPK被5-氨基咪唑-4-羧酰胺核苷（AICAR）或噻唑烷二酮罗格列酮激活时，观察到细胞生长受到抑制。因此，暴露于其中一种或两种药物4天后，雄激素非依赖型（DU145， PO）和雄激素敏感型（LNCaP）细胞的生长抑制率达到90%。在研究中，这与丙二醇辅酶a（一种新脂肪酸合成的中间体）浓度的降低和细胞周期抑制剂p21表达的增加有关。此外，AICAR抑制了参与蛋白质合成的两个关键酶mTOR和p70S6K，阻断了雄激素R1881促进细胞生长的能力和LNCaP细胞中两种新的脂肪酸合成酶乙酰辅酶a羧化酶和脂肪酸合成酶的表达。结果表明AMPK是治疗前列腺癌的潜在靶点。(C) 2004爱思唯尔公司版权所有。
Prostate cancer cells require high rates of de novo fatty acid synthesis and protein synthesis for their rapid growth. We report here that the growth of these cells is markedly diminished by incubation with activators of AMP-activated protein kinase (AMPK), a fuel-sensing enzyme that has been shown to diminish both of these processes in intact tissues. Inhibition of cell growth was observed when AMPK was activated by either 5-aminoimidazole-4-carboxamide riboside (AICAR) or the thiazolidinedione rosiglitazone. Thus, a 90% inhibition of the growth of androgen-independent (DU145, PO) and androgen-sensitive (LNCaP) cells was achieved after 4 days of exposure to one or both of these agents. Where Studied, this was associated with a decrease in the concentration of malonyl CoA, an intermediate of de novo fatty acid synthesis, and an increase in expression of the cell cycle inhibitor p21. In addition, AICAR inhibited two key enzymes involved in protein synthesis, mTOR and p70S6K, and blocked the ability of the androgen R1881 to increase cell growth and the expression of two enzymes for de novo fatty acid synthesis, acetyl CoA carboxylase and fatty acid synthase, in the LNCaP cells. The results suggest that AMPK is a potential target for the treatment of prostate cancer. (C) 2004 Elsevier Inc. All rights reserved.