TY - JOUR
T1 - Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells
AU - Fujiwara, Chiaki
AU - Muramatsu, Yukiko
AU - Nishii, Megumi
AU - Tokunaka, Kazuhiro
AU - Tahara, Hidetoshi
AU - Ueno, Masaru
AU - Yamori, Takao
AU - Sugimoto, Yoshikazu
AU - Seimiya, Hiroyuki
N1 - Funding Information:
We would like to thank Dr. Kyotaro Hirashima for evaluating siRNAs, Tomoko Oh-hara and Michiko Sakamoto for performing TRAP assays and Hiroko Sawada for performing RT-PCR. We are also grateful to Dr. Zou Songyang for providing anti-TIN2, anti-TPP1 and anti-RAP1 antibodies; Dr. Titia de Lange for providing antiPOT1 and anti-RIF1 antibodies; Dr. Tokichi Miyakawa for providing yeast strains. We thank the Screening Committee of New Anticancer Agents supported by Grant-in-Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science and Technology, Japan for evaluation of JFCR39 cell sensitivities to MST-312, and the Molecular Profiling Committee, Grant-in-Aid for Scientific Research on Innovative Areas “Platform of Advanced Animal Model Support” from The Ministry of Education, Culture, Sports, Science and Technology, Japan (KAKENHI 16H06276) for evaluation of the effect of MST-312 on cell phenotype. We also thank members of the Seimiya lab for invaluable discussions. This work was supported in part by Grants-in-Aid for Scientific Research, Japan Society for the Promotion of Science (JSPS) [Scientific Research (B) 16H04716 to HS, Challenging Exploratory Research 24650639 to HS and Challenging Research (Exploratory) 18K19487 to HS] and Grants-in-Aid for Scientific Research, The Ministry of Education, Culture, Sports, Science and Technology (MEXT) (Innovative Areas 18H04633 to HS), a research grant from Kobayashi Foundation for Cancer Research (to HS) and Japan Agency for Medical Research and Development (AMED, 16cm0106102h0001 to HS). Funding for open access charge: [Japan Society for the Promotion of Science/16H04716]. A draft of this manuscript was commercially edited by Edanz Group (www.edanzediting.com/ac).
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41598-018-33139-x
DO - 10.1038/s41598-018-33139-x
M3 - Article
C2 - 30287851
AN - SCOPUS:85054424584
SN - 2045-2322
VL - 8
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 14827
ER -
