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標題: Aurora A 專一性抑制劑MLN8237造成細胞中Aurora A表現增加及中心粒異常
A selective Aurora A inhibitor, MLN8237, induces cellular Aurora A expression increase and centrosomal abnormality.
作者: 張智瑩
Chih-Ying Chang
關鍵字: Aurora A;MLN8237(Alisertib);中心粒;p53;Aurora A;MLN8237(Alisertib);centrosome;p53
在過去文獻中細胞週期中G1期→S期→G2期→M期四期,而有絲分裂(M期) 則是在細胞週期扮演非常重要的一環,並且受到細胞外因子或是細胞內訊息傳遞所調控,且在不同的文獻中也提到當癌症發生時Aurora A會有過度表現的現象,因此也被當作是治療癌症指標之一。而在不同年份中的文獻中也指出Aurora kinase A (Aurora A) 是絲氨酸/蘇氨酸激酶 (Serine/Threonine kinases) 是Aurora kinase家族成員之一,主要參與在調控有絲分裂 (Mitotic progression) 和減數分裂 (Meiosis progression) 的過程,其中包含了中心體 (Centrosome) 的形成、使雙極紡錘體 (Spindle) 伸長、DNA解聚 (Decondensation) 和後期核膜重建,以及細胞移動 (Cell locomotion) 以及細胞極性化作用 (Cell polarity) 上扮演重要角色。Alisertib (MLN8237) 是一種Aurora A選擇性小分子抑制劑,是從先前分子Alisertib開發的用於治療晚期惡性腫瘤的選擇性小分子AAK (Aurora A kinase) 抑製劑,並在許多癌症治療中作為單一藥物開發中,並會和其他藥物做合併使用。當我們將MLN8237用於生長快速的胚胎腎元細胞 (HEK293),我們發現到了各式蛋白質的表現量上升如:Cyclin B1、Cyclin D1,表示了在MLN8237處理下,細胞週期的進展受到了影響,細胞週期停留在G2/M期,但在偶然情況下將藥物處理於非小細胞肺癌 (H1299) 發現了Aurora A的蛋白質表現量隨著劑量的上升有顯著性上升的趨勢,也觀察了Aurora A的mRNA (AurkA) 表現量隨之上升,並且在免疫螢光染色方面證實了加入MLN8237藥物會使的染色體、中心粒的異常,並會使的Aurora A明顯的累積性增加,也在HeLa細胞中發現了Aurora A蛋白質的增加以及p53蛋白質的減少,很有可能MLN8237藥物會透過Aurora A和p53之間負向調控而影響Aurora A的增加,本次研究所發現的結果在臨床應用具有一定程度的貢獻,且對治療時提供了一些應注意的事項。

Aurora A is a serine/threonine kinase which primarily localizes in the centrosome and mitotic spindle and responds for centrosome maturation, separation, spindle formation and mitotic entry. Therefore, Aurora A plays an important regulator to mitosis and meiosis as well as the regulation of cell proliferation. The oncogenic role of Aurora A has also been explored in recent years and its inhibition becomes a relevant issue in cancer therapy. MLN8237 (Alisertib) is a specific inhibitor of Aurora A which has been currently under evaluation of cancer clinical trial. In our present results treating the fast-growing cell line, HEK293, with MLN8237 (0-500 nM ), we found the protein levels of Cyclin B1 and Cyclin D1 were increased, suggesting the progress of G2/M phase in cell cycle was affected. It reflects the reason why MLN8237 can be used to treat cancer. Accidentally, the protein levels of Aurora A was significantly increased after MLN8237 treatment. Several lines of evidence also address similar findings without detailed mechanism and discussion. In addition to protein levels, the real time Q-PCR data indicated that Aurora A mRNA (Aurk A) was also increased after MLN8237 treatment. And p53 protein levels and Q-PCR data was also decreased after MLN8237 treatment. In summary, MLN8237 is a potential drug for future cancer therapy; however, the treatment might lead to the increasing gene expression of itself. The physiological negative feedback might be one of the reasons to explain the phenomenon. Meanwhile, the combination treatment against Aurora A expression with its kinase inhibitor might be beneficial to comprehensively block Aurora A actions in cell proliferation inhibition, polyploidy, mitotic catastrophe and multiple centrosome.
Rights: 同意授權瀏覽/列印電子全文服務,2021-08-30起公開。
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