據(jù)科學(xué)家在2月17日Cell上的報(bào)道,，抑制通過(guò)延伸染色體兩端的保護(hù)帽從破壞中搶救惡性細(xì)胞的端粒酶,，殺死腫瘤細(xì)胞但也觸發(fā)引起癌癥存活和傳播的耐藥性通路。
端粒酶在許多晚期癌癥中過(guò)度表達(dá),，但是評(píng)價(jià)它作為治療靶標(biāo)的潛力要求我們理解它做什么且它如何做,。
我們利用小鼠的實(shí)驗(yàn)性優(yōu)點(diǎn)來(lái)造模，并更精確地研究在癌癥發(fā)育,、進(jìn)展和治療中的端粒危機(jī),、端粒酶復(fù)活和端粒酶消除。這個(gè)精巧的模型揭示了兩種機(jī)制,，包括一種被癌細(xì)胞用于適應(yīng)端粒酶喪失的意料之外的代謝通路,。
這些發(fā)現(xiàn)讓我們預(yù)期腫瘤細(xì)胞可能對(duì)端粒酶抑制怎樣反應(yīng)，突出開(kāi)發(fā)靶向端粒酶和這些適應(yīng)性耐藥機(jī)制的藥物聯(lián)合的需要,。
研究人員用實(shí)驗(yàn)對(duì)端粒酶作為治療靶標(biāo)進(jìn)行了評(píng)估,。在正常細(xì)胞中，端粒酶活性性或缺失,，正常細(xì)胞在染色體末端有細(xì)胞分裂期間保護(hù)DNA穩(wěn)定性的稱為調(diào)聚物的重復(fù)核苷酸片段,。
隨首每一次分裂端粒變短，最后導(dǎo)致基因組不穩(wěn)定和細(xì)胞死亡,，術(shù)稱"端粒危機(jī)",。在癌癥中，端粒酶在端粒危機(jī)期間變得活躍并通過(guò)延長(zhǎng)端粒搶救基因組上異常的細(xì)胞,。（生物谷bioon.com）
doi:10.1016/j.cell.2011.12.028
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Antitelomerase Therapy Provokes ALT and Mitochondrial Adaptive Mechanisms in Cancer
Jian Hu,Soyoon Sarah Hwang,Marc Liesa,Boyi Gan,Ergun Sahin,Mariela Jaskelioff,Zhihu Ding,Haoqiang Ying,Adam T. Boutin,Hailei Zhang,Shawn Johnson,Elena Ivanova,Maria Kost-Alimova,Alexei Protopopov,Yaoqi Alan Wang,Orian S. Shirihai,Lynda Chin,Ronald A. DePinho
Summary To assess telomerase as a cancer therapeutic target and determine adaptive mechanisms to telomerase inhibition, we modeled telomerase reactivation and subsequent extinction in T cell lymphomas arising in Atm?/?mice engineered with an inducible telomerase reverse transcriptase allele. Telomerase reactivation in the setting of telomere dysfunction enabled full malignant progression with alleviation of telomere dysfunction-induced checkpoints. These cancers possessed copy number alterations targeting key loci in human T cell lymphomagenesis. Upon telomerase extinction, tumor growth eventually slowed with reinstatement of telomere dysfunction-induced checkpoints, yet growth subsequently resumed as tumors acquired alternative lengthening of telomeres (ALT) and aberrant transcriptional networks centering on mitochondrial biology and oxidative defense. ALT+ tumors acquired amplification/overexpression of PGC-1β, a master regulator of mitochondrial biogenesis and function, and they showed marked sensitivity to PGC-1β or SOD2 knockdown. Genetic modeling of telomerase extinction reveals vulnerabilities that motivate coincidental inhibition of mitochondrial maintenance and oxidative defense mechanisms to enhance antitelomerase cancer therapy.
