2月17日,，Cell雜志發(fā)表了美國德克薩斯大學和達納法伯癌癥研究所（Dana-Farber Cancer Institute）等處科學家的研究成果,。研究發(fā)現(xiàn)，抗端粒酶療法能夠誘發(fā)腫瘤細胞的端粒通過同源重組維持其長度,，線粒體也會產(chǎn)生適應(yīng)機制,。
端粒酶是癌組織中特異表達的關(guān)鍵酶,與腫瘤細胞無限增殖關(guān)系密切,。為評估端粒酶作為癌癥治療的靶點和端粒酶抑制后的適應(yīng)機制,，研究人員設(shè)計了有可誘導(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淋巴細胞中端粒酶激活和隨后消失的過程,。
癌細胞的一個顯著特點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胞中仍有重要功能，尤其是通過ALT（alternative lengthening of telomeres）即同源重組維持端粒長度的癌細胞,。
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胞越過端粒功能異常所誘發(fā)的檢驗點,，加速腫瘤生長,。端粒酶活性消失后，腫瘤生長會減速,，因為端粒功能異常誘發(fā)的檢驗點又發(fā)揮其功能,。然而，腫瘤隨后又恢復(fù)生長,，這是由于腫瘤細胞獲得了ALT,，即通過同源重組的方法維持端粒的長度，而后依賴于線粒體和氧化防御作用進行轉(zhuǎn)錄,。ALT+的腫瘤中PGC-1β過表達,，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PGC-1β和SOD2 敲除非常敏感,。
研究表明,，在抑制端粒酶活性時，再同時抑制線粒體和氧化防御功能,，抗端粒酶腫瘤療法將會更有效,。（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.
