Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1).
Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1).
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DOI：
10.1038/srep42504
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发表时间：
2017-02-15
影响因子：
4.6
通讯作者：
Leong CO
中科院分区：
文献类型：
--
作者：
Chung FF;Tan PF;Raja VJ;Tan BS;Lim KH;Kam TS;Hii LW;Tan SH;See SJ;Tan YF;Wong LZ;Yam WK;Mai CW;Bradshaw TD;Leong CO
前体mRNA （pre-mRNA）剪接是由一个被称为剪接体的大型核糖核蛋白复合物催化的。大量研究表明，剪接体成分（包括剪接因子3b亚基1 (SF3B1)）的异常剪接模式或突变与标志性癌症表型相关。这导致了具有剪接体调节活性的小分子作为潜在抗癌剂的鉴定和开发。Jerantinine A （JA）是一种新型吲哚类生物碱，通过抑制微管蛋白聚合和诱导G2/M细胞周期阻滞，对人癌细胞表现出较强的抗增殖活性。利用组合全基因组shRNA文库筛选和全局蛋白质组学分析，我们发现JA通过上调乳腺癌细胞中的SF3B1和SF3B3蛋白来靶向剪接体。值得注意的是，JA诱导了显著的肿瘤特异性细胞死亡和未剪接的pre- mrna显著增加。相比之下，内源性SF3B1的缺失消除了JA诱导的凋亡效应，但没有消除G2/M细胞周期阻滞。进一步的分析表明，JA稳定了乳腺癌细胞中内源性SF3B1蛋白，并诱导该蛋白与核小体复合物分离。总之，这些结果表明，除了报道的靶向微管蛋白聚合外，JA还通过靶向SF3B1和SF3B3发挥其抗肿瘤活性。
Precursor mRNA (pre-mRNA) splicing is catalyzed by a large ribonucleoprotein complex known as the spliceosome. Numerous studies have indicated that aberrant splicing patterns or mutations in spliceosome components, including the splicing factor 3b subunit 1 (SF3B1), are associated with hallmark cancer phenotypes. This has led to the identification and development of small molecules with spliceosome-modulating activity as potential anticancer agents. Jerantinine A (JA) is a novel indole alkaloid which displays potent anti-proliferative activities against human cancer cell lines by inhibiting tubulin polymerization and inducing G2/M cell cycle arrest. Using a combined pooled-genome wide shRNA library screen and global proteomic profiling, we showed that JA targets the spliceosome by up-regulating SF3B1 and SF3B3 protein in breast cancer cells. Notably, JA induced significant tumor-specific cell death and a significant increase in unspliced pre-mRNAs. In contrast, depletion of endogenous SF3B1 abrogated the apoptotic effects, but not the G2/M cell cycle arrest induced by JA. Further analyses showed that JA stabilizes endogenous SF3B1 protein in breast cancer cells and induced dissociation of the protein from the nucleosome complex. Together, these results demonstrate that JA exerts its antitumor activity by targeting SF3B1 and SF3B3 in addition to its reported targeting of tubulin polymerization.