Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells

Scientific Reports

Kazuhiro Tokunaka¹  Hidetoshi Tahara²  Megumi Nishii³  Masaru Ueno³  Yoshikazu Sugimoto⁴  Yukiko Muramatsu⁵  Hiroyuki Seimiya⁵  Chiaki Fujiwara⁵  Takao Yamori⁶ 

[1] Biomedicine Group, Pharmaceutical Research Laboratories, Pharmaceuticals Group, Nippon Kayaku Co., Ltd.;Department of Cellular and Molecular Biology, Division of Integrated Medical Science, Graduate School of Biomedical Sciences, Hiroshima University;Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University;Division of Chemotherapy, Faculty of Pharmacy, Keio University;Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research;Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research;

关键词: Telomerase Inhibition;    Telomerase Activity;    Acute Deleterious Effects;    Telomere Shortening;    Hutchinson-Gilford Progeria Syndrome (HGPS);   

DOI  :  10.1038/s41598-018-33139-x

来源: DOAJ

【 摘 要 】

Abstract 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.

【 授权许可】

Unknown