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Nature:干扰剪接体的功能或可有效杀灭恶性癌细胞

来源:生物谷 2015-09-07 13:47

2015年9月7日 讯 /生物谷BIOON/ --癌症通常就像是油门踏板失控的汽车一样失控驰骋在路上而无法控制,大多数新型的靶向癌症疗法都试图寻找解决癌症“油门踩踏”的问题来解决癌症的发展,但对于很多类型的癌症而言,失控的油门踏板似乎得不到修复,因此科学家们急需一种新型替代疗法,而近日一项刊登于国际杂志Nature上的研究论文中,来自贝勒医学院的科学家通过研究发现了如何抑制一些致死性癌症的新思路。

研究者Thomas F. Westbrook教授表示,大约30%的恶性癌症都是由癌症基因MYC所驱动的,而目前并没有人可以关闭该基因的表达,而且MYC驱动的癌症患者通常会缺少有效的治疗手段;就好象造成汽车失控的情况一样,研究者已经发现了一种新型方法来杀灭由MYC驱动的癌症,而通过抑制癌细胞中剪接体的功能或许就可以有效抑制癌症的进展。

研究者指出,我们发现由MYC驱动的癌症依赖于剪接体来生存,剪接体是一种由多种蛋白质组成的复杂分子机器,其可以帮助癌症阅读剔除必要步骤后的指令,当抑制剪接体功能后,癌细胞就不再理解生长和生存的细胞指令了。这项研究中研究人员发现,利用杀灭肿瘤细胞的药物就可以实现对剪接体的抑制,但会在未受影响的小鼠机体中留下非癌变的组织。

MYC会重新连接癌细胞并且改变很多情况,比如所有肿瘤细胞需要的结构单元的产生等,但这种连接往往会给癌细胞带来新的压力及弱点,如果我们可以学会如何加剧这些压力,那么或许就可以在不伤害正常组织的情况下杀灭癌细胞。当剪接体抑制子不能够提供解决所有癌症的答案时,其或许就可以作为一种候选靶点来帮助治疗某些恶性癌症,比如三阴性乳腺癌等。(生物谷Bioon.com)

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The spliceosome is a therapeutic vulnerability in MYC-driven cancer

Tiffany Y.-T. Hsu, Lukas M. Simon, Nicholas J. Neill, Richard Marcotte, Azin Sayad, Christopher S. Bland, Gloria V. Echeverria, Tingting Sun, Sarah J. Kurley, Siddhartha Tyagi, Kristen L. Karlin, Rocio Dominguez-Vidaña, Jessica D. Hartman, Alexander Renwick, Kathleen Scorsone, Ronald J. Bernardi, Samuel O. Skinner, Antrix Jain, Mayra Orellana, Chandraiah Lagisetti, Ido Golding, Sung Y. Jung, Joel R. Neilson, Xiang H.-F. Zhang, Thomas A. Cooper et al.

MYC (also known as c-MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. MYC is a transcription factor, and many of its pro-tumorigenic functions have been attributed to its ability to regulate gene expression programs1, 2, 3. Notably, oncogenic MYC activation has also been shown to increase total RNA and protein production in many tissue and disease contexts4, 5, 6, 7. While such increases in RNA and protein production may endow cancer cells with pro-tumour hallmarks, this increase in synthesis may also generate new or heightened burden on MYC-driven cancer cells to process these macromolecules properly8. Here we discover that the spliceosome is a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene in human mammary epithelial cells, and demonstrate that BUD31 is a component of the core spliceosome required for its assembly and catalytic activity. Core spliceosomal factors (such as SF3B1 and U2AF1) associated with BUD31 are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total precursor messenger RNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Notably, genetic or pharmacological inhibition of the spliceosome in vivo impairs survival, tumorigenicity and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing, and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers.

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