端粒
端粒酶
端粒酶逆转录酶
免疫系统
癌症研究
DNA损伤
敏化
逆转录酶
癌症
衰老
生物
分子生物学
免疫学
DNA
细胞生物学
遗传学
聚合酶链反应
基因
作者
Yue Liu,Rick C. Betori,Joanna Pagacz,Grant Frost,Elena V. Efimova,Ding Wu,Donald Wolfgeher,Tracy M. Bryan,Scott B. Cohen,Karl A. Scheidt,Stephen J. Kron
标识
DOI:10.1016/j.chembiol.2022.09.002
摘要
Beyond synthesizing telomere repeats, the telomerase reverse transcriptase (TERT) also serves multiple other roles supporting cancer growth. Blocking telomerase to drive telomere erosion appears impractical, but TERT's non-canonical activities have yet to be fully explored as cancer targets. Here, we used an irreversible TERT inhibitor, NU-1, to examine impacts on resistance to conventional cancer therapies. In vitro, inhibiting TERT sensitized cells to chemotherapy and radiation. NU-1 delayed repair of double-strand breaks, resulting in persistent DNA damage signaling and cellular senescence. Although NU-1 alone did not impact growth of syngeneic CT26 tumors in BALB/c mice, it dramatically enhanced the effects of radiation, leading to immune-dependent tumor elimination. Tumors displayed persistent DNA damage, suppressed proliferation, and increased activated immune infiltrate. Our studies confirm TERT's role in limiting genotoxic effects of conventional therapy but also implicate TERT as a determinant of immune evasion and therapy resistance.
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