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Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo
Despite recent advances in cancer management and therapy, resistance to cytotoxic medications remains a major clinical challenge; hence, combination-based anti-cancer treatment regimens are currently gaining momentum. PTC-209 reduced BMI1 protein expression, while palbociclib inhibited CDK4, Rb, and...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757061/ https://www.ncbi.nlm.nih.gov/pubmed/31548560 http://dx.doi.org/10.1038/s41598-019-50140-0 |
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author | Elango, Ramesh Vishnubalaji, Radhakrishnan Manikandan, Muthurangan Binhamdan, Sarah Ibrahim Siyal, Abdul-Aziz Alshawakir, Yasser A. Alfayez, Musaad Aldahmash, Abdullah Alajez, Nehad M. |
author_facet | Elango, Ramesh Vishnubalaji, Radhakrishnan Manikandan, Muthurangan Binhamdan, Sarah Ibrahim Siyal, Abdul-Aziz Alshawakir, Yasser A. Alfayez, Musaad Aldahmash, Abdullah Alajez, Nehad M. |
author_sort | Elango, Ramesh |
collection | PubMed |
description | Despite recent advances in cancer management and therapy, resistance to cytotoxic medications remains a major clinical challenge; hence, combination-based anti-cancer treatment regimens are currently gaining momentum. PTC-209 reduced BMI1 protein expression, while palbociclib inhibited CDK4, Rb, and pRb(Ser795) protein expression in MDA-MB-231 cells. PTC-209 and palbociclib exhibited dose-dependent cytotoxic effects against MDA-MB-231 (breast), HCT116 (colon), and PC-3 (prostate) models, which was more profound in the combination group. Transcriptome and pathway analyses revealed inhibition of insulin signaling, focal adhesion, DNA damage response, and Wnt/pluripotency signaling pathways as well as cell proliferation, and cellular movement functional categories by PTC-209. Transcriptome and pathway analyses revealed palbociclib to mainly affect cell cycle progression and survival. Upstream analysis identified several networks affected by PTC-209 (EZH2, IFNB1, TRIB3, EGFR, SREBF1, IL1A, ERG, TGFB1, MAX, MNT) and palbociclib (RABL6, MITF, RARA, TAL1, AREG, E2F3, FOXM1, ESR1, ERBB2, and E2F). PTC-209 and palbociclib reduced colony and sphere formation, cell migration, and cell viability, which was further enhanced in the combination group. Concordantly, combination of PTC-209 and palbociclib exhibited more profound effects on MDA-MB-231 tumor formation in vivo. Our data suggest concurrent targeting of BMI1 and CDK4/CDK6 might provide novel therapeutic opportunity for breast, colon, and prostate cancer. |
format | Online Article Text |
id | pubmed-6757061 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-67570612019-10-02 Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo Elango, Ramesh Vishnubalaji, Radhakrishnan Manikandan, Muthurangan Binhamdan, Sarah Ibrahim Siyal, Abdul-Aziz Alshawakir, Yasser A. Alfayez, Musaad Aldahmash, Abdullah Alajez, Nehad M. Sci Rep Article Despite recent advances in cancer management and therapy, resistance to cytotoxic medications remains a major clinical challenge; hence, combination-based anti-cancer treatment regimens are currently gaining momentum. PTC-209 reduced BMI1 protein expression, while palbociclib inhibited CDK4, Rb, and pRb(Ser795) protein expression in MDA-MB-231 cells. PTC-209 and palbociclib exhibited dose-dependent cytotoxic effects against MDA-MB-231 (breast), HCT116 (colon), and PC-3 (prostate) models, which was more profound in the combination group. Transcriptome and pathway analyses revealed inhibition of insulin signaling, focal adhesion, DNA damage response, and Wnt/pluripotency signaling pathways as well as cell proliferation, and cellular movement functional categories by PTC-209. Transcriptome and pathway analyses revealed palbociclib to mainly affect cell cycle progression and survival. Upstream analysis identified several networks affected by PTC-209 (EZH2, IFNB1, TRIB3, EGFR, SREBF1, IL1A, ERG, TGFB1, MAX, MNT) and palbociclib (RABL6, MITF, RARA, TAL1, AREG, E2F3, FOXM1, ESR1, ERBB2, and E2F). PTC-209 and palbociclib reduced colony and sphere formation, cell migration, and cell viability, which was further enhanced in the combination group. Concordantly, combination of PTC-209 and palbociclib exhibited more profound effects on MDA-MB-231 tumor formation in vivo. Our data suggest concurrent targeting of BMI1 and CDK4/CDK6 might provide novel therapeutic opportunity for breast, colon, and prostate cancer. Nature Publishing Group UK 2019-09-23 /pmc/articles/PMC6757061/ /pubmed/31548560 http://dx.doi.org/10.1038/s41598-019-50140-0 Text en © The Author(s) 2019 Open Access 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 http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Elango, Ramesh Vishnubalaji, Radhakrishnan Manikandan, Muthurangan Binhamdan, Sarah Ibrahim Siyal, Abdul-Aziz Alshawakir, Yasser A. Alfayez, Musaad Aldahmash, Abdullah Alajez, Nehad M. Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo |
title | Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo |
title_full | Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo |
title_fullStr | Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo |
title_full_unstemmed | Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo |
title_short | Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo |
title_sort | concurrent targeting of bmi1 and cdk4/6 abrogates tumor growth in vitro and in vivo |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757061/ https://www.ncbi.nlm.nih.gov/pubmed/31548560 http://dx.doi.org/10.1038/s41598-019-50140-0 |
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