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Inhibition of the PLK1‐Coupled Cell Cycle Machinery Overcomes Resistance to Oxaliplatin in Colorectal Cancer
Dysregulation of the cell cycle machinery leads to genomic instability and is a hallmark of cancer associated with chemoresistance and poor prognosis in colorectal cancer (CRC). Identifying and targeting aberrant cell cycle machinery is expected to improve current therapies for CRC patients. Here,up...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8655181/ https://www.ncbi.nlm.nih.gov/pubmed/34881526 http://dx.doi.org/10.1002/advs.202100759 |
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author | Yu, Zhaoliang Deng, Peng Chen, Yufeng Liu, Shini Chen, Jinghong Yang, Zihuan Chen, Jianfeng Fan, Xinjuan Wang, Peili Cai, Zerong Wang, Yali Hu, Peishan Lin, Dezheng Xiao, Rong Zou, Yifeng Huang, Yan Yu, Qiang Lan, Ping Tan, Jing Wu, Xiaojian |
author_facet | Yu, Zhaoliang Deng, Peng Chen, Yufeng Liu, Shini Chen, Jinghong Yang, Zihuan Chen, Jianfeng Fan, Xinjuan Wang, Peili Cai, Zerong Wang, Yali Hu, Peishan Lin, Dezheng Xiao, Rong Zou, Yifeng Huang, Yan Yu, Qiang Lan, Ping Tan, Jing Wu, Xiaojian |
author_sort | Yu, Zhaoliang |
collection | PubMed |
description | Dysregulation of the cell cycle machinery leads to genomic instability and is a hallmark of cancer associated with chemoresistance and poor prognosis in colorectal cancer (CRC). Identifying and targeting aberrant cell cycle machinery is expected to improve current therapies for CRC patients. Here,upregulated polo‐like kinase 1 (PLK1) signaling, accompanied by deregulation of cell cycle‐related pathways in CRC is identified. It is shown that aberrant PLK1 signaling correlates with recurrence and poor prognosis in CRC patients. Genetic and pharmacological blockade of PLK1 significantly increases the sensitivity to oxaliplatin in vitro and in vivo. Mechanistically, transcriptomic profiling analysis reveals that cell cycle‐related pathways are activated by oxaliplatin treatment but suppressed by a PLK1 inhibitor. Cell division cycle 7 (CDC7) is further identified as a critical downstream effector of PLK1 signaling, which is transactivated via the PLK1‐MYC axis. Increased CDC7 expression is also found to be positively correlated with aberrant PLK1 signaling in CRC and is associated with poor prognosis. Moreover, a CDC7 inhibitor synergistically enhances the anti‐tumor effect of oxaliplatin in CRC models, demonstrating the potential utility of targeting the PLK1‐MYC‐CDC7 axis in the treatment of oxaliplatin‐based chemotherapy. |
format | Online Article Text |
id | pubmed-8655181 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-86551812021-12-20 Inhibition of the PLK1‐Coupled Cell Cycle Machinery Overcomes Resistance to Oxaliplatin in Colorectal Cancer Yu, Zhaoliang Deng, Peng Chen, Yufeng Liu, Shini Chen, Jinghong Yang, Zihuan Chen, Jianfeng Fan, Xinjuan Wang, Peili Cai, Zerong Wang, Yali Hu, Peishan Lin, Dezheng Xiao, Rong Zou, Yifeng Huang, Yan Yu, Qiang Lan, Ping Tan, Jing Wu, Xiaojian Adv Sci (Weinh) Research Articles Dysregulation of the cell cycle machinery leads to genomic instability and is a hallmark of cancer associated with chemoresistance and poor prognosis in colorectal cancer (CRC). Identifying and targeting aberrant cell cycle machinery is expected to improve current therapies for CRC patients. Here,upregulated polo‐like kinase 1 (PLK1) signaling, accompanied by deregulation of cell cycle‐related pathways in CRC is identified. It is shown that aberrant PLK1 signaling correlates with recurrence and poor prognosis in CRC patients. Genetic and pharmacological blockade of PLK1 significantly increases the sensitivity to oxaliplatin in vitro and in vivo. Mechanistically, transcriptomic profiling analysis reveals that cell cycle‐related pathways are activated by oxaliplatin treatment but suppressed by a PLK1 inhibitor. Cell division cycle 7 (CDC7) is further identified as a critical downstream effector of PLK1 signaling, which is transactivated via the PLK1‐MYC axis. Increased CDC7 expression is also found to be positively correlated with aberrant PLK1 signaling in CRC and is associated with poor prognosis. Moreover, a CDC7 inhibitor synergistically enhances the anti‐tumor effect of oxaliplatin in CRC models, demonstrating the potential utility of targeting the PLK1‐MYC‐CDC7 axis in the treatment of oxaliplatin‐based chemotherapy. John Wiley and Sons Inc. 2021-10-28 /pmc/articles/PMC8655181/ /pubmed/34881526 http://dx.doi.org/10.1002/advs.202100759 Text en © 2021 The Authors. Advanced Science published by Wiley‐VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Yu, Zhaoliang Deng, Peng Chen, Yufeng Liu, Shini Chen, Jinghong Yang, Zihuan Chen, Jianfeng Fan, Xinjuan Wang, Peili Cai, Zerong Wang, Yali Hu, Peishan Lin, Dezheng Xiao, Rong Zou, Yifeng Huang, Yan Yu, Qiang Lan, Ping Tan, Jing Wu, Xiaojian Inhibition of the PLK1‐Coupled Cell Cycle Machinery Overcomes Resistance to Oxaliplatin in Colorectal Cancer |
title | Inhibition of the PLK1‐Coupled Cell Cycle Machinery Overcomes Resistance to Oxaliplatin in Colorectal Cancer |
title_full | Inhibition of the PLK1‐Coupled Cell Cycle Machinery Overcomes Resistance to Oxaliplatin in Colorectal Cancer |
title_fullStr | Inhibition of the PLK1‐Coupled Cell Cycle Machinery Overcomes Resistance to Oxaliplatin in Colorectal Cancer |
title_full_unstemmed | Inhibition of the PLK1‐Coupled Cell Cycle Machinery Overcomes Resistance to Oxaliplatin in Colorectal Cancer |
title_short | Inhibition of the PLK1‐Coupled Cell Cycle Machinery Overcomes Resistance to Oxaliplatin in Colorectal Cancer |
title_sort | inhibition of the plk1‐coupled cell cycle machinery overcomes resistance to oxaliplatin in colorectal cancer |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8655181/ https://www.ncbi.nlm.nih.gov/pubmed/34881526 http://dx.doi.org/10.1002/advs.202100759 |
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