Ansamycin antibiotics inhibit Akt activation and cyclin D expression in breast cancer cells that overexpress HER2
Ansamycin antibiotics inhibit Akt activation and cyclin D expression in breast cancer cells that overexpress HER2
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DOI：
10.1038/sj.onc.1205184
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发表时间：
2002-02-14
期刊：
影响因子：
8
通讯作者：
Rosen, N
中科院分区：
文献类型：
--
作者：
Basso, AD;Solit, DB;Rosen, N
安莎霉素抗生素，如17-烯丙基氨基格尔德霉素（17-AAG），结合到热休克蛋白90和调节其功能，导致蛋白酶体降解的一个子集的信号蛋白，需要热休克蛋白90的构象成熟。HER 2是这些药物的一个非常敏感的靶标。安莎霉素引起RB依赖性G1期阻滞，其与通过PI 3激酶、Akt依赖性途径的D-细胞周期蛋白的损失相关。D-cyclin的下调部分是由于Akt表达的丧失。此外，在HER 2过表达的乳腺癌细胞中，17-AAG在Akt蛋白发生任何变化之前引起Akt活性的快速抑制。安莎霉素类;导致HER 2快速降解，同时丧失HER 3相关PI 3激酶活性。这导致Akt活性的丧失、Akt底物的去磷酸化和D-细胞周期蛋白表达的丧失。向细胞中引入组成性膜结合形式的PI 3激酶阻止了药物对Akt活性和D-细胞周期蛋白的影响。因此，在具有高HER 2的乳腺癌细胞中，Akt被HER 2/HER 3异二聚体激活是D-细胞周期蛋白表达所需的。在小鼠异种移植模型中，无毒剂量的17-AAG显著降低了HER 2的表达和Akt的磷酸化，并抑制了肿瘤生长。因此，Akt活化的药理学抑制可通过安莎霉素实现，并且可用于治疗HER 2驱动的肿瘤。
Ansamycin antibiotics, such as 17-allylaminogeldanamycin (17-AAG), bind to Hsp90 and regulate its function, resulting in the proteasomal degradation of a subset of signaling proteins that require Hsp90 for conformational maturation. HER2 is a very sensitive target of these drugs. Ansamycins cause RB-dependent G1 arrest that is associated with loss of D-cyclins via a PI3 kinase, Akt dependent pathway. Downregulation of D-cyclin was due, in part, to loss of Akt expression in response to drug. Moreover, in HER2 overexpressing breast cancer cells, 17-AAG caused rapid inhibition of Akt activity prior to any change in Akt protein. Ansamycins; caused rapid degradation of HER2 and a concomitant loss in HER3 associated PI3 kinase activity. This led to a loss of Akt activity, dephosphorylation of Akt substrates, and loss of D-cyclin expression. Introduction into cells of a constitutively membrane bound form of PI3 kinase prevented the effects of the drug on Akt activity and D-cyclins. Thus, in breast cancer cells with high HER2, Akt activation by HER2/HER3 heterodimers; is required for D-cyclin expression. In murine xenograft models, non-toxic doses of 17-AAG markedly reduced the expression of HER2 and phosphorylation of Akt and inhibited tumor growth. Thus, pharmacological inhibition of Akt activation is achievable with ansamycins and may be useful for the treatment of HER2 driven tumors.