Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells.
Chiaki FujiwaraYukiko MuramatsuMegumi NishiiKazuhiro TokunakaHidetoshi TaharaMasaru UenoTakao YamoriYoshikazu SugimotoHiroyuki SeimiyaPublished in: Scientific reports (2018)
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.
Keyphrases
- dna damage
- dna damage response
- oxidative stress
- liver failure
- dna repair
- respiratory failure
- drug induced
- circulating tumor
- single cell
- cell free
- diabetic rats
- single molecule
- endothelial cells
- aortic dissection
- endoplasmic reticulum stress
- cell therapy
- cell cycle arrest
- poor prognosis
- cell death
- hepatitis b virus
- binding protein
- nucleic acid
- intensive care unit
- cell proliferation
- bone marrow
- gene expression
- pi k akt
- mesenchymal stem cells
- induced pluripotent stem cells
- mechanical ventilation
- acute respiratory distress syndrome
- amino acid