Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
Mol Cancer. 2010 Jun 17;9:153. doi: 10.1186/1476-4598-9-153.
Centrosome aberrations can cause genomic instability and correlate with malignant progression in common human malignancies such as breast and prostate cancer. Deregulation of cyclin/cyclin-dependent kinase 2 (CDK2) activity has previously been shown to be critically involved in centrosome overduplication. We therefore test here whether small molecule CDK inhibitors derived from the bis-indole indirubin can be used to suppress centrosome aberrations as a novel approach to chemoprevention of malignant progression.
As expected, we found that the CDK inhibitor indirubin-3'-oxime (IO) suppresses centrosome amplification in breast cancer cells. However, we made the unexpected discovery that indirubin-derived compounds that have been chemically modified to be inactive as kinase inhibitors such as 1-methyl-indirubin-3'-oxime (MeIO) still significantly reduced centrosome amplification. All indirubins used in the present study are potent agonists of the aryl hydrocarbon receptor (AhR), which is known for its important role in the cellular metabolism of xenobiotics. To corroborate our results, we first show that the coincidence of nuclear AhR overexpression, reflecting a constitutive activation, and numerical centrosome aberrations correlates significantly with malignancy in mammary tissue specimens. Remarkably, a considerable proportion (72.7%) of benign mammary tissue samples scored also positive for nuclear AhR overexpression. We furthermore provide evidence that continued expression of endogenous AhR is critical to promote centriole overduplication induced by cyclin E and that AhR and cyclin E may function in the same pathway. Overexpression of the AhR in the absence of exogenous ligands was found to rapidly disrupt centriole duplication control. Nonetheless, the AhR agonists IO and MeIO were still found to significantly reduce centriole overduplication stimulated by ectopic AhR expression.
Our results indicate that continued expression of endogenous AhR promotes centrosome amplification in breast cancer cells in a pathway that involves cyclin E. AhR agonists such as indirubins inhibit centrosome amplification even when stimulated by ectopic expression of the AhR suggesting that these compounds are potentially useful for the chemoprevention of centrosome-mediated cell division errors and malignant progression in neoplasms in which the AhR is overexpressed. Future studies are warranted to determine whether individuals in which nuclear AhR overexpression is detected in benign mammary tissue are at a higher risk for developing pre-cancerous or cancerous breast lesions.
中心体异常可导致基因组不稳定，并与常见人类恶性肿瘤（如乳腺癌和前列腺癌）的恶性进展相关。先前的研究表明，细胞周期蛋白/细胞周期蛋白依赖性激酶 2（CDK2）活性的失调与中心体过度复制密切相关。因此，我们在这里测试小分子 CDK 抑制剂是否可以从双吲哚靛蓝衍生而来，以抑制中心体异常，作为预防恶性进展的新方法。
正如预期的那样，我们发现 CDK 抑制剂靛玉红-3'-肟（IO）可抑制乳腺癌细胞的中心体扩增。然而，我们有了意想不到的发现，即化学修饰后失去激酶抑制活性的靛蓝衍生化合物，如 1-甲基靛玉红-3'-肟（MeIO），仍然显著减少中心体扩增。本研究中使用的所有靛蓝都是芳烃受体（AhR）的有效激动剂，AhR 因其在外源化学物质的细胞代谢中的重要作用而闻名。为了证实我们的结果，我们首先表明，核 AhR 过表达的巧合，反映了组成型激活，以及数值中心体异常与乳腺组织标本的恶性程度显著相关。值得注意的是，相当一部分（72.7%）良性乳腺组织标本的核 AhR 过表达也呈阳性。我们进一步提供证据表明，内源性 AhR 的持续表达对于促进 cyclin E 诱导的中心粒过度复制至关重要，并且 AhR 和 cyclin E 可能在同一途径中发挥作用。发现 AhR 在没有外源性配体的情况下过表达会迅速破坏中心粒复制控制。尽管如此，AhR 激动剂 IO 和 MeIO 仍被发现可显著减少由异位 AhR 表达刺激的中心粒过度复制。
我们的结果表明，内源性 AhR 的持续表达通过 cyclin E 促进乳腺癌细胞中心体扩增。AhR 激动剂，如靛蓝，即使在 AhR 过表达刺激时也能抑制中心体扩增，这表明这些化合物可能对预防 AhR 过表达的肿瘤中中心体介导的细胞分裂错误和恶性进展有用。未来的研究需要确定在良性乳腺组织中检测到核 AhR 过表达的个体是否有更高的风险发展为癌前或癌性乳腺病变。
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