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一种 microRNA 筛选方法,用于鉴定 BCL2 抑制剂 ABT-263(navitoclax)敏感性的调节剂。

A microRNA screen to identify modulators of sensitivity to BCL2 inhibitor ABT-263 (navitoclax).

机构信息

Global Pharmaceutical Research and Development, Abbott, Building AP-10, Department R4CD, 100 Abbott Park Road, Abbott Park, IL 60064, USA.

出版信息

Mol Cancer Ther. 2010 Nov;9(11):2943-50. doi: 10.1158/1535-7163.MCT-10-0427. Epub 2010 Sep 9.

Abstract

Evasion of apoptosis is a known feature of cancer cells. One mechanism of deregulating the apoptotic pathway is through overexpression of antiapoptotic BCL2 family members. ABT-263 (navitoclax) is a first-in-class BCL2 family inhibitor that restores the ability of cancer cells to undergo apoptosis. However, many cancer cells are resistant to ABT-263 due to high levels of a BCL2 family member, MCL1, which is not targeted by the drug. MCL1 expression is regulated transcriptionally, translationally, and through proteasome-mediated degradation. Recently, MCL1 expression was shown to be affected by microRNAs (miRNA). To identify miRNAs that modulate the sensitivity of cancer cells to ABT-263, we screened a library of 810 human miRNA mimics in HCT-116 cells in the presence of ABT-263. The screen revealed 19 miRNAs that sensitize HCT-116 cells to ABT-263. Fifteen of these miRNAs were also shown to sensitize CHL1 melanoma cells to the same agent. We further evaluated 12 of the strongest sensitizers in these cell lines. We found that these sensitizers induced apoptosis only in the presence of ABT-263. In addition, whereas all 12 of these miRNAs reduced MCL1 protein expression, only 10 of them targeted MCL1 through direct binding to the 3'-untranslated region of the gene, raising the possibility that other resistance regulators of MCL1 expression may be identified using our method. Finally, because sensitizing miRNA expression is lower in tumors compared with normal tissues, our data can facilitate the design of miRNA replacement therapies to increase sensitivity to BCL2 antagonists.

摘要

细胞凋亡逃逸是癌细胞的一个已知特征。一种调节细胞凋亡途径的机制是通过过度表达抗凋亡 BCL2 家族成员。ABT-263(navitoclax)是一种首创的 BCL2 家族抑制剂,可恢复癌细胞发生细胞凋亡的能力。然而,由于高水平的 BCL2 家族成员 MCL1,许多癌细胞对 ABT-263 产生耐药性,而该药物不能靶向 MCL1。MCL1 的表达受转录、翻译和蛋白酶体介导的降解调控。最近,MCL1 的表达被证明受到 microRNAs(miRNA)的影响。为了确定调节癌细胞对 ABT-263 敏感性的 miRNA,我们在存在 ABT-263 的情况下筛选了 HCT-116 细胞中 810 个人类 miRNA 模拟物文库。该筛选揭示了 19 种 miRNA 可使 HCT-116 细胞对 ABT-263 敏感。其中 15 种 miRNA 也可使 CHL1 黑色素瘤细胞对同一药物敏感。我们进一步评估了这两种细胞系中 12 种最强的敏化剂。我们发现这些敏化剂仅在存在 ABT-263 的情况下诱导细胞凋亡。此外,虽然这 12 种 miRNA 都降低了 MCL1 蛋白表达,但只有 10 种通过直接结合基因的 3'-非翻译区靶向 MCL1,这表明使用我们的方法可能会鉴定出其他调节 MCL1 表达的耐药调节剂。最后,由于肿瘤中敏化 miRNA 的表达低于正常组织,我们的数据可以促进 miRNA 替代疗法的设计,以增加对 BCL2 拮抗剂的敏感性。

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