2月17日，Cell雜志發(fā)表了美國(guó)德克薩斯大學(xué)和達(dá)納法伯癌癥研究所（Dana-Farber Cancer Institute）等處科學(xué)家的研究成果,。研究發(fā)現(xiàn),，抗端粒酶療法能夠誘發(fā)腫瘤細(xì)胞的端粒通過(guò)同源重組維持其長(zhǎng)度,，線粒體也會(huì)產(chǎn)生適應(yīng)機(jī)制。
端粒酶是癌組織中特異表達(dá)的關(guān)鍵酶,與腫瘤細(xì)胞無(wú)限增殖關(guān)系密切,。為評(píng)估端粒酶作為癌癥治療的靶點(diǎn)和端粒酶抑制后的適應(yīng)機(jī)制,，研究人員設(shè)計(jì)了有可誘導(dǎo)的端粒酶的逆轉(zhuǎn)錄酶亞基等位基因的Atm-/-小鼠模型，而后模仿了T淋巴細(xì)胞中端粒酶激活和隨后消失的過(guò)程,。
癌細(xì)胞的一個(gè)顯著特點(diǎn)是依賴于糖分解代謝而不是線粒體供能,，但是線粒體在腫瘤細(xì)胞中仍有重要功能，尤其是通過(guò)ALT（alternative lengthening of telomeres）即同源重組維持端粒長(zhǎng)度的癌細(xì)胞,。
研究發(fā)現(xiàn),，在端粒功能喪失的情況下，端粒酶重激活可以幫助細(xì)胞越過(guò)端粒功能異常所誘發(fā)的檢驗(yàn)點(diǎn)，加速腫瘤生長(zhǎng),。端粒酶活性消失后,，腫瘤生長(zhǎng)會(huì)減速，因?yàn)槎肆９δ墚惓ＵT發(fā)的檢驗(yàn)點(diǎn)又發(fā)揮其功能,。然而,，腫瘤隨后又恢復(fù)生長(zhǎng)，這是由于腫瘤細(xì)胞獲得了ALT,，即通過(guò)同源重組的方法維持端粒的長(zhǎng)度,，而后依賴于線粒體和氧化防御作用進(jìn)行轉(zhuǎn)錄。ALT+的腫瘤中PGC-1β過(guò)表達(dá),，PGC-1β是線粒體發(fā)生和線粒體功能的主要調(diào)節(jié)子,，ALT+的腫瘤對(duì)PGC-1β和SOD2 敲除非常敏感。
研究表明,，在抑制端粒酶活性時(shí),，再同時(shí)抑制線粒體和氧化防御功能，抗端粒酶腫瘤療法將會(huì)更有效,。（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
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.
