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

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Cell Proliferation* ; DNA Damage* ; DNA Repair*; Lamin Type A/*metabolism ; Neoplasms/*pathology ; Telomere/*metabolism; Artificial Cells ; Benzamides/metabolism ; Cell Line, Tumor ; Enzyme Inhibitors/metabolism ; Humans ; Peptide Mapping ; Sensitivity and Specificity ; Telomerase/antagonists & inhibitors ; Topoisomerase II Inhibitors/metabolism

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.

Mol Cancer Ther. 2002 Jul;1(9):657-65. (PMID: 12479362)
J Cell Sci. 2006 Nov 15;119(Pt 22):4644-9. (PMID: 17062639)
Cancer Res. 1996 Jan 1;56(1):218-22. (PMID: 8548767)
Nat Rev Genet. 2010 May;11(5):319-30. (PMID: 20351727)
Mol Cancer Ther. 2017 Apr;16(4):752-762. (PMID: 28179481)
Science. 2003 Jun 27;300(5628):2055. (PMID: 12702809)
Nat Rev Cancer. 2008 Mar;8(3):167-79. (PMID: 18256617)
J Natl Cancer Inst. 1990 Jul 4;82(13):1107-12. (PMID: 2359136)
Nat Commun. 2015 Aug 24;6:8044. (PMID: 26299252)
EMBO J. 2000 Jun 1;19(11):2652-61. (PMID: 10835362)
Cell. 1997 Mar 7;88(5):593-602. (PMID: 9054499)
Science. 2005 Aug 19;309(5738):1253-6. (PMID: 16037417)
EMBO J. 2009 Aug 19;28(16):2414-27. (PMID: 19629036)
Cancer Res. 1999 Aug 15;59(16):4042-9. (PMID: 10463605)
Nature. 2003 May 15;423(6937):293-8. (PMID: 12714972)
Science. 1998 Nov 20;282(5393):1484-7. (PMID: 9822378)
Cell Cycle. 2011 Aug 1;10(15):2549-60. (PMID: 21701264)
J Cell Sci. 2002 Jan 1;115(Pt 1):61-70. (PMID: 11801724)
Science. 2015 May 29;348(6238):1036-9. (PMID: 25977370)
J Natl Cancer Inst. 2006 Apr 19;98(8):545-56. (PMID: 16622124)
Cell. 1999 May 14;97(4):515-25. (PMID: 10338215)
Genes Environ. 2015 Oct 01;37:13. (PMID: 27350809)
Genes Dev. 2005 Sep 15;19(18):2100-10. (PMID: 16166375)
Nat Genet. 2017 Mar;49(3):349-357. (PMID: 28135248)
J Clin Invest. 2004 Feb;113(3):370-8. (PMID: 14755334)
Nat Med. 2005 Jul;11(7):780-5. (PMID: 15980864)
Nucleic Acids Res. 2015 Feb 27;43(4):2022-32. (PMID: 25653161)
J Biol Chem. 2005 Jun 24;280(25):23709-17. (PMID: 15831499)
Cancer Res. 1991 Oct 1;51(19):5275-83. (PMID: 1717144)
Mol Cell Biol. 2013 Aug;33(15):2988-95. (PMID: 23716593)
Cell. 1993 Jul 2;73(7):1267-79. (PMID: 8324822)
Science. 1994 Dec 23;266(5193):2011-5. (PMID: 7605428)
Cancer Res. 2003 Jul 15;63(14):3931-9. (PMID: 12873987)
Mol Cell Biol. 2004 Mar;24(5):1944-55. (PMID: 14966275)
Nature. 2003 Nov 13;426(6963):194-8. (PMID: 14608368)
Sci Rep. 2017 Jun 15;7(1):3605. (PMID: 28620243)
Oncotarget. 2016 May 31;7(22):31639-51. (PMID: 27192120)
Mol Cancer Ther. 2018 Jun;17(6):1187-1195. (PMID: 29563163)
Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12606-11. (PMID: 12193655)
Oncotarget. 2017 May 23;8(21):34045-34056. (PMID: 28423660)
Curr Biol. 2000 Oct 19;10(20):1299-302. (PMID: 11069113)
Biochem Biophys Res Commun. 1998 Aug 19;249(2):391-6. (PMID: 9712707)
J Cell Sci. 2010 Aug 1;123(Pt 15):2605-12. (PMID: 20605919)
Cell. 2013 Jan 31;152(3):584-98. (PMID: 23374351)
EMBO J. 2001 Dec 17;20(24):6958-68. (PMID: 11742973)
Cancer Cell. 2005 Jan;7(1):25-37. (PMID: 15652747)
Mol Cell Biol. 2002 Jan;22(1):332-42. (PMID: 11739745)
Genes Dev. 2002 Mar 1;16(5):533-47. (PMID: 11877373)
Cancer Res. 2004 Jul 15;64(14):4833-40. (PMID: 15256453)
Science. 1998 Jan 16;279(5349):349-52. (PMID: 9454332)
Cancer Res. 1999 Aug 15;59(16):4004-11. (PMID: 10463599)
Bioorg Med Chem. 2012 Mar 15;20(6):1947-51. (PMID: 22336246)
Nat Rev Mol Cell Biol. 2017 Mar;18(3):175-186. (PMID: 28096526)
Am J Physiol Cell Physiol. 2015 Mar 1;308(5):C372-7. (PMID: 25518961)
J Natl Cancer Inst. 2005 May 18;97(10):765-77. (PMID: 15900046)
Science. 2006 May 19;312(5776):1059-63. (PMID: 16645051)
J Cell Sci. 2001 Dec;114(Pt 24):4567-73. (PMID: 11792821)
Ann Oncol. 2015 Feb;26(2):354-62. (PMID: 25467017)
Nature. 2005 Aug 18;436(7053):1048-52. (PMID: 16107853)
Biosci Biotechnol Biochem. 2006 Oct;70(10):2451-9. (PMID: 17031058)
Cell. 1997 Oct 3;91(1):25-34. (PMID: 9335332)
Clin Cancer Res. 2013 Dec 1;19(23):6578-84. (PMID: 24097866)
Nature. 2011 Apr 14;472(7342):221-5. (PMID: 21346760)
Cancer Discov. 2016 Jun;6(6):584-93. (PMID: 27029895)
Nat Methods. 2005 Nov;2(11):829-31. (PMID: 16278652)
Oncogene. 1994 Sep;9(9):2649-53. (PMID: 8058329)
Mol Cancer Res. 2016 Apr;14(4):315-23. (PMID: 26941407)
Cell. 1999 May 14;97(4):503-14. (PMID: 10338214)

24650639 International Japan Society for the Promotion of Science (JSPS); 18K19487 International Japan Society for the Promotion of Science (JSPS); N/A International Kobayashi Foundation for Cancer Research; 16cm0106102h0001 International Japan Agency for Medical Research and Development (AMED); 18H04633 International Ministry of Education, Culture, Sports, Science, and Technology (MEXT)

0 (Benzamides)
0 (Enzyme Inhibitors)
0 (Lamin Type A)
0 (MST 312)
0 (Topoisomerase II Inhibitors)
EC 2.7.7.49 (Telomerase)

Date Created: 20181006 Date Completed: 20191024 Latest Revision: 20191024

20221213

PMC6172206

10.1038/s41598-018-33139-x

30287851