Peroxisome proliferator-activated receptor γ-independent ablation of cyclin D1 by thiazolidinediones and their derivatives in breast cancer cells
Peroxisome proliferator-activated receptor γ-independent ablation of cyclin D1 by thiazolidinediones and their derivatives in breast cancer cells
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DOI：
10.1124/mol.104.007732
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发表时间：
2005-04-01
影响因子：
3.6
通讯作者：
Chen, CS
中科院分区：
文献类型：
--
作者：
Huang, JW;Shiau, CW;Chen, CS
鉴于乳腺癌中靶向细胞周期蛋白D1的临床相关性，我们研究了过氧化物酶体增殖物激活受体γ（PPAR γ）激动剂曲格列酮和环格列酮对细胞周期蛋白D1抑制作用的机制。我们获得的证据表明，高剂量的曲格列酮和环格列酮抑制细胞周期蛋白D1的能力是独立的过氧化物酶体增殖物激活受体γ激活。在MCF-7细胞中，无PPAR γ活性的曲格列酮和环格列酮类似物5-[4-（6-羟基-2，5，7，8-四甲基-苯并二氢吡喃-2基-甲氧基）-亚苄基]-2，4-噻唑烷二酮（Delta 2-TG）和5-[4-（1-甲基-环己基甲氧基）-亚苄基]-噻唑烷2，4-二酮能够促进细胞周期蛋白D1的消融，其效力与曲格列酮和环格列酮相似。逆转录-聚合酶链反应显示，细胞周期蛋白D1的mRNA水平保持不变，在药物处理的细胞，表明抑制是在转录后水平介导的。此外，这些药物的消融作用是特异性的细胞周期蛋白D1，在许多其他细胞周期蛋白和细胞周期蛋白依赖性激酶的表达水平检查药物治疗后保持不变。我们的数据表明，曲格列酮和Delta 2-TG诱导的细胞周期蛋白D1抑制是通过蛋白酶体促进的蛋白水解介导的，因为它被不同的蛋白酶体抑制剂抑制，包括N-苄氧羰基-L-亮氨酰-L-亮氨酰-L-正亮氨酸（MG 132），lactacystin和epoxomicin，并且之前增加泛素化。这两种药理活性的分离（即，PPARgamma激活和细胞周期蛋白D1消融）提供了分子基础，使用Delta 2-TG作为支架，开发一类新的细胞周期蛋白D1消融剂。因此，我们合成了一系列Delta 2-TG衍生物。其中，5-[4-（6-烯丙氧基-2，5，7，8-四甲基-苯并二氢吡喃-2-基-甲氧基）-亚苄基]-2，4-噻唑烷二酮代表了结构优化的药剂，其在细胞周期蛋白D1抑制和MCF-7细胞生长抑制方面的效力比Delta 2-TG高一个数量级。
In light of the clinical relevance of targeting cyclin D1 in breast cancer, we have investigated the mechanism underlying the effect of the peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists troglitazone and ciglitazone on cyclin D1 repression. We obtain evidence that the ability of high doses of troglitazone and ciglitazone to repress cyclin D1 is independent of PPAR gamma activation. PPAR gamma-inactive troglitazone and ciglitazone analogs 5-[4-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2yl-methoxy)-benzylidene]-2,4-thiazolidinedione (Delta 2-TG) and 5-[4-(1-methyl-cyclohexylmethoxy)-benzylidene]-thiazolidine2,4-dione are able to facilitate cyclin D1 ablation with potency similar to that of troglitazone and ciglitazone in MCF-7 cells. Reverse transcription-polymerase chain reaction shows that the mRNA level of cyclin D1 remains unaltered in drug-treated cells, indicating the repression is mediated at the post-transcriptional level. Moreover, the ablative effect of these agents is specific to cyclin D1, in that the expression levels of many other cyclins and cyclin-dependent kinases examined remain unchanged after drug treatment. Our data indicate that troglitazone- and Delta 2-TG-induced cyclin D1 repression is mediated via proteasome-facilitated proteolysis because it is inhibited by different proteasome inhibitors, including N-carbobenzoxy-L-leucinyl-L-leucinyl-L-norleucinal (MG132), lactacystin, and epoxomicin, and is preceded by increased ubiquitination. The dissociation of these two pharmacological activities (i.e., PPAR gamma activation and cyclin D1 ablation) provides a molecular basis to use Delta 2-TG as a scaffold to develop a novel class of cyclin D1-ablative agents. Therefore, a series of Delta 2-TG derivatives have been synthesized. Among them, 5-[4-(6-allyoxy-2,5,7,8-tetramethyl-chroman-2-yl-methoxy)-benzylidene]-2,4-thiazolidinedione represents a structurally optimized agent with potency that is an order of magnitude higher than that of Delta 2-TG in cyclin D1 repression and MCF-7 cell growth inhibition.