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Inhibitors of telomerase and poly(ADP-ribose) polymerases synergize to limit the lifespan of pancreatic cancer cells
Imetelstat (GRN163L) is a potent and selective inhibitor of telomerase. We have previously reported that GRN163L could shorten telomeres and limit the lifespan of CD18/HPAF and CAPAN1 pancreatic cancer cells. Here, we examined the effects of GRN163L on two other pancreatic cancer cell lines: AsPC1 a...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663552/ https://www.ncbi.nlm.nih.gov/pubmed/29137380 http://dx.doi.org/10.18632/oncotarget.19410 |
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author | Burchett, Katrina M. Etekpo, Asserewou Batra, Surinder K. Yan, Ying Ouellette, Michel M. |
author_facet | Burchett, Katrina M. Etekpo, Asserewou Batra, Surinder K. Yan, Ying Ouellette, Michel M. |
author_sort | Burchett, Katrina M. |
collection | PubMed |
description | Imetelstat (GRN163L) is a potent and selective inhibitor of telomerase. We have previously reported that GRN163L could shorten telomeres and limit the lifespan of CD18/HPAF and CAPAN1 pancreatic cancer cells. Here, we examined the effects of GRN163L on two other pancreatic cancer cell lines: AsPC1 and L3.6pl. In both lines, chronic exposure to GRN163L led to an initial shortening of telomeres followed by a stabilization of extremely short telomeres. In AsPC1 cells, telomere attrition eventually led to the induction of crisis and the loss of the treated population. In L3.6pl cells, crisis was transient and followed by the emergence of GRN163L-resistant cells, which could grow at increasing concentrations of GRN163L. The Shelterin complex is a telomere-associated complex that limits the access of telomerase to telomeres. The telomerase inhibitory function of this complex can be enhanced by drugs that block the poly(ADP-ribosyl)ation of its TRF1 and/or TRF2 subunits. Combined treatment of the GRN163L-resistant L3.6pl cells with GRN163L and 3-aminobenzamide (3AB), a general inhibitor of poly(ADP-ribose) polymerases, led to additional telomere shortening and limited the lifespan of the resistant cells. Results from this work suggest that inhibitors of telomerase and poly(ADP-ribose) polymerases can cooperate to limit the lifespan of pancreatic cancer cells. |
format | Online Article Text |
id | pubmed-5663552 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-56635522017-11-13 Inhibitors of telomerase and poly(ADP-ribose) polymerases synergize to limit the lifespan of pancreatic cancer cells Burchett, Katrina M. Etekpo, Asserewou Batra, Surinder K. Yan, Ying Ouellette, Michel M. Oncotarget Research Paper Imetelstat (GRN163L) is a potent and selective inhibitor of telomerase. We have previously reported that GRN163L could shorten telomeres and limit the lifespan of CD18/HPAF and CAPAN1 pancreatic cancer cells. Here, we examined the effects of GRN163L on two other pancreatic cancer cell lines: AsPC1 and L3.6pl. In both lines, chronic exposure to GRN163L led to an initial shortening of telomeres followed by a stabilization of extremely short telomeres. In AsPC1 cells, telomere attrition eventually led to the induction of crisis and the loss of the treated population. In L3.6pl cells, crisis was transient and followed by the emergence of GRN163L-resistant cells, which could grow at increasing concentrations of GRN163L. The Shelterin complex is a telomere-associated complex that limits the access of telomerase to telomeres. The telomerase inhibitory function of this complex can be enhanced by drugs that block the poly(ADP-ribosyl)ation of its TRF1 and/or TRF2 subunits. Combined treatment of the GRN163L-resistant L3.6pl cells with GRN163L and 3-aminobenzamide (3AB), a general inhibitor of poly(ADP-ribose) polymerases, led to additional telomere shortening and limited the lifespan of the resistant cells. Results from this work suggest that inhibitors of telomerase and poly(ADP-ribose) polymerases can cooperate to limit the lifespan of pancreatic cancer cells. Impact Journals LLC 2017-07-20 /pmc/articles/PMC5663552/ /pubmed/29137380 http://dx.doi.org/10.18632/oncotarget.19410 Text en Copyright: © 2017 Burchett et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Burchett, Katrina M. Etekpo, Asserewou Batra, Surinder K. Yan, Ying Ouellette, Michel M. Inhibitors of telomerase and poly(ADP-ribose) polymerases synergize to limit the lifespan of pancreatic cancer cells |
title | Inhibitors of telomerase and poly(ADP-ribose) polymerases synergize to limit the lifespan of pancreatic cancer cells |
title_full | Inhibitors of telomerase and poly(ADP-ribose) polymerases synergize to limit the lifespan of pancreatic cancer cells |
title_fullStr | Inhibitors of telomerase and poly(ADP-ribose) polymerases synergize to limit the lifespan of pancreatic cancer cells |
title_full_unstemmed | Inhibitors of telomerase and poly(ADP-ribose) polymerases synergize to limit the lifespan of pancreatic cancer cells |
title_short | Inhibitors of telomerase and poly(ADP-ribose) polymerases synergize to limit the lifespan of pancreatic cancer cells |
title_sort | inhibitors of telomerase and poly(adp-ribose) polymerases synergize to limit the lifespan of pancreatic cancer cells |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663552/ https://www.ncbi.nlm.nih.gov/pubmed/29137380 http://dx.doi.org/10.18632/oncotarget.19410 |
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