期刊
SCIENTIFIC REPORTS
卷 8, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-018-33139-x
关键词
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资金
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Molecular Profiling Committee
- Ministry of Education, Culture, Sports, Science and Technology, Japan [KAKENHI 16H06276]
- Japan Society for the Promotion of Science (JSPS) [16H04716, 24650639, 18K19487]
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) [18H04633]
- Kobayashi Foundation for Cancer Research
- Japan Agency for Medical Research and Development (AMED) [16cm0106102h0001]
- Japan Society for the Promotion of Science [16H04716]
Telomere maintenance by telomerase activity supports the infinite growth of cancer cells. MST-312, a synthetic telomerase inhibitor, gradually shortens telomeres at non-acute lethal doses and eventually induces senescence and apoptosis of telomerase-positive cancer cells. Here we report that MST-312 at higher doses works as a dual inhibitor of telomerase and DNA topoisomerase II and exhibits acute anti-proliferative effects on cancer cells and xenografted tumours in vivo. Our cell-based chemical fingerprinting approach revealed that cancer cells with shorter telomeres and lower expression of lamin A, a nuclear architectural protein, exhibited higher sensitivity to the acute deleterious effects of MST-312, accompanied by formation of telomere dysfunction-induced foci and DNA double-strand breaks. Telomere elongation and lamin A overexpression attenuated telomeric and non-telomeric DNA damage, respectively, and both conferred resistance to apoptosis induced by MST-312 and other DNA damaging anticancer agents. These observations suggest that sufficient pools of telomeres and a nuclear lamina component contribute to the cellular robustness against DNA damage induced by therapeutic treatment in human cancer cells.
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