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Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro

BACKGROUND: The mitotic arrest deficiency protein 2 (MAD2) is a key component of the mitotic spindle assembly checkpoint, monitoring accurate chromosomal alignment at the metaphase plate before mitosis. MAD2 also has a function in cellular senescence and in a cell's response to microtubule inhi...

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Autores principales: Prencipe, M, Fitzpatrick, P, Gorman, S, Mosetto, M, Klinger, R, Furlong, F, Harrison, M, O'Connor, D, Roninson, I B, O'Sullivan, J, McCann, A
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2788249/
https://www.ncbi.nlm.nih.gov/pubmed/19935801
http://dx.doi.org/10.1038/sj.bjc.6605419
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author Prencipe, M
Fitzpatrick, P
Gorman, S
Mosetto, M
Klinger, R
Furlong, F
Harrison, M
O'Connor, D
Roninson, I B
O'Sullivan, J
McCann, A
author_facet Prencipe, M
Fitzpatrick, P
Gorman, S
Mosetto, M
Klinger, R
Furlong, F
Harrison, M
O'Connor, D
Roninson, I B
O'Sullivan, J
McCann, A
author_sort Prencipe, M
collection PubMed
description BACKGROUND: The mitotic arrest deficiency protein 2 (MAD2) is a key component of the mitotic spindle assembly checkpoint, monitoring accurate chromosomal alignment at the metaphase plate before mitosis. MAD2 also has a function in cellular senescence and in a cell's response to microtubule inhibitory (MI) chemotherapy exemplified by paclitaxel. METHODS: Using an siRNA approach, the impact of MAD2 down-regulation on cellular senescence and paclitaxel responsiveness was investigated. The endpoints of senescence, cell viability, migration, cytokine expression, cell cycle analysis and anaphase bridge scoring were carried out using standard approaches. RESULTS: We show that MAD2 down-regulation induces premature senescence in the MCF7 breast epithelial cancer cell line. These MAD2-depleted (MAD2↓) cells are also significantly replicative incompetent but retain viability. Moreover, they show significantly higher levels of anaphase bridges and polyploidy compared to controls. In addition, these cells secrete higher levels of IL-6 and IL-8 representing key components of the senescence-associated secretory phenotype (SASP) with the ability to impact on neighbouring cells. In support of this, MAD2↓ cells show enhanced migratory ability. At 72 h after paclitaxel, MAD2↓ cells show a significant further induction of senescence compared with paclitaxel naive controls. In addition, there are significantly more viable cells in the MAD2↓ MCF7 cell line after paclitaxel reflecting the observed increase in senescence. CONCLUSION: Considering that paclitaxel targets actively dividing cells, these senescent cells will evade cytotoxic kill. In conclusion, compromised MAD2 levels induce a population of senescent cells resistant to paclitaxel.
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spelling pubmed-27882492010-12-01 Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro Prencipe, M Fitzpatrick, P Gorman, S Mosetto, M Klinger, R Furlong, F Harrison, M O'Connor, D Roninson, I B O'Sullivan, J McCann, A Br J Cancer Molecular Diagnostics BACKGROUND: The mitotic arrest deficiency protein 2 (MAD2) is a key component of the mitotic spindle assembly checkpoint, monitoring accurate chromosomal alignment at the metaphase plate before mitosis. MAD2 also has a function in cellular senescence and in a cell's response to microtubule inhibitory (MI) chemotherapy exemplified by paclitaxel. METHODS: Using an siRNA approach, the impact of MAD2 down-regulation on cellular senescence and paclitaxel responsiveness was investigated. The endpoints of senescence, cell viability, migration, cytokine expression, cell cycle analysis and anaphase bridge scoring were carried out using standard approaches. RESULTS: We show that MAD2 down-regulation induces premature senescence in the MCF7 breast epithelial cancer cell line. These MAD2-depleted (MAD2↓) cells are also significantly replicative incompetent but retain viability. Moreover, they show significantly higher levels of anaphase bridges and polyploidy compared to controls. In addition, these cells secrete higher levels of IL-6 and IL-8 representing key components of the senescence-associated secretory phenotype (SASP) with the ability to impact on neighbouring cells. In support of this, MAD2↓ cells show enhanced migratory ability. At 72 h after paclitaxel, MAD2↓ cells show a significant further induction of senescence compared with paclitaxel naive controls. In addition, there are significantly more viable cells in the MAD2↓ MCF7 cell line after paclitaxel reflecting the observed increase in senescence. CONCLUSION: Considering that paclitaxel targets actively dividing cells, these senescent cells will evade cytotoxic kill. In conclusion, compromised MAD2 levels induce a population of senescent cells resistant to paclitaxel. Nature Publishing Group 2009-12-01 2009-11-24 /pmc/articles/PMC2788249/ /pubmed/19935801 http://dx.doi.org/10.1038/sj.bjc.6605419 Text en Copyright © 2009 Cancer Research UK https://creativecommons.org/licenses/by/4.0/This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/.
spellingShingle Molecular Diagnostics
Prencipe, M
Fitzpatrick, P
Gorman, S
Mosetto, M
Klinger, R
Furlong, F
Harrison, M
O'Connor, D
Roninson, I B
O'Sullivan, J
McCann, A
Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro
title Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro
title_full Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro
title_fullStr Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro
title_full_unstemmed Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro
title_short Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro
title_sort cellular senescence induced by aberrant mad2 levels impacts on paclitaxel responsiveness in vitro
topic Molecular Diagnostics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2788249/
https://www.ncbi.nlm.nih.gov/pubmed/19935801
http://dx.doi.org/10.1038/sj.bjc.6605419
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