2月17日，Cell杂志发表了美国德克萨斯大学和达纳法伯癌症研究所（Dana-Farber Cancer Institute）等处科学家的研究成果。研究发现，抗端粒酶疗法能够诱发肿瘤细胞的端粒通过同源重组维持其长度，线粒体也会产生适应机制。
端粒酶是癌组织中特异表达的关键酶,与肿瘤细胞无限增殖关系密切。为评估端粒酶作为癌症治疗的靶点和端粒酶抑制后的适应机制，研究人员设计了有可诱导的端粒酶的逆转录酶亚基等位基因的Atm-/-小鼠模型，而后模仿了T淋巴细胞中端粒酶激活和随后消失的过程。
癌细胞的一个显著特点是依赖于糖分解代谢而不是线粒体供能，但是线粒体在肿瘤细胞中仍有重要功能，尤其是通过ALT（alternative lengthening of telomeres）即同源重组维持端粒长度的癌细胞。
研究发现，在端粒功能丧失的情况下，端粒酶重激活可以帮助细胞越过端粒功能异常所诱发的检验点，加速肿瘤生长。端粒酶活性消失后，肿瘤生长会减速，因为端粒功能异常诱发的检验点又发挥其功能。然而，肿瘤随后又恢复生长，这是由于肿瘤细胞获得了ALT，即通过同源重组的方法维持端粒的长度，而后依赖于线粒体和氧化防御作用进行转录。ALT+的肿瘤中PGC-1β过表达，PGC-1β是线粒体发生和线粒体功能的主要调节子，ALT+的肿瘤对PGC-1β和SOD2 敲除非常敏感。
研究表明，在抑制端粒酶活性时，再同时抑制线粒体和氧化防御功能，抗端粒酶肿瘤疗法将会更有效。（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.
