Cargando…
Reversing tozasertib resistance in glioma through inhibition of pyruvate dehydrogenase kinases
Acquired resistance to conventional chemotherapeutic agents limits their effectiveness and can cause cancer treatment to fail. Because enzymes in the aurora kinase family are vital regulators of several mitotic events, we reasoned that targeting these kinases with tozasertib, a pan‐aurora kinase inh...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8732347/ https://www.ncbi.nlm.nih.gov/pubmed/34058053 http://dx.doi.org/10.1002/1878-0261.13025 |
_version_ | 1784627567147352064 |
---|---|
author | Jane, Esther P. Premkumar, Daniel R. Rajasundaram, Dhivyaa Thambireddy, Swetha Reslink, Matthew C. Agnihotri, Sameer Pollack, Ian F. |
author_facet | Jane, Esther P. Premkumar, Daniel R. Rajasundaram, Dhivyaa Thambireddy, Swetha Reslink, Matthew C. Agnihotri, Sameer Pollack, Ian F. |
author_sort | Jane, Esther P. |
collection | PubMed |
description | Acquired resistance to conventional chemotherapeutic agents limits their effectiveness and can cause cancer treatment to fail. Because enzymes in the aurora kinase family are vital regulators of several mitotic events, we reasoned that targeting these kinases with tozasertib, a pan‐aurora kinase inhibitor, would not only cause cytokinesis defects, but also induce cell death in high‐grade pediatric and adult glioma cell lines. We found that tozasertib induced cell cycle arrest, increased mitochondrial permeability and reactive oxygen species generation, inhibited cell growth and migration, and promoted cellular senescence and pro‐apoptotic activity. However, sustained exposure to tozasertib at clinically relevant concentrations conferred resistance, which led us to examine the mechanistic basis for the emergence of drug resistance. RNA‐sequence analysis revealed a significant upregulation of the gene encoding pyruvate dehydrogenase kinase isoenzyme 4 (PDK4), a pyruvate dehydrogenase (PDH) inhibitory kinase that plays a crucial role in the control of metabolic flexibility under various physiological conditions. Upregulation of PDK1, PDK2, PDK3, or PDK4 protein levels was positively correlated with tozasertib‐induced resistance through inhibition of PDH activity. Tozasertib‐resistant cells exhibited increased mitochondrial mass as measured by 10‐N‐nonyl‐Acridine Orange. Inhibition of PDK with dichloroacetate resulted in increased mitochondrial permeability and cell death in tozasertib‐resistant glioma cell lines. Based on these results, we believe that PDK is a selective target for the tozasertib resistance phenotype and should be considered for further preclinical evaluations. |
format | Online Article Text |
id | pubmed-8732347 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-87323472022-01-11 Reversing tozasertib resistance in glioma through inhibition of pyruvate dehydrogenase kinases Jane, Esther P. Premkumar, Daniel R. Rajasundaram, Dhivyaa Thambireddy, Swetha Reslink, Matthew C. Agnihotri, Sameer Pollack, Ian F. Mol Oncol Research Articles Acquired resistance to conventional chemotherapeutic agents limits their effectiveness and can cause cancer treatment to fail. Because enzymes in the aurora kinase family are vital regulators of several mitotic events, we reasoned that targeting these kinases with tozasertib, a pan‐aurora kinase inhibitor, would not only cause cytokinesis defects, but also induce cell death in high‐grade pediatric and adult glioma cell lines. We found that tozasertib induced cell cycle arrest, increased mitochondrial permeability and reactive oxygen species generation, inhibited cell growth and migration, and promoted cellular senescence and pro‐apoptotic activity. However, sustained exposure to tozasertib at clinically relevant concentrations conferred resistance, which led us to examine the mechanistic basis for the emergence of drug resistance. RNA‐sequence analysis revealed a significant upregulation of the gene encoding pyruvate dehydrogenase kinase isoenzyme 4 (PDK4), a pyruvate dehydrogenase (PDH) inhibitory kinase that plays a crucial role in the control of metabolic flexibility under various physiological conditions. Upregulation of PDK1, PDK2, PDK3, or PDK4 protein levels was positively correlated with tozasertib‐induced resistance through inhibition of PDH activity. Tozasertib‐resistant cells exhibited increased mitochondrial mass as measured by 10‐N‐nonyl‐Acridine Orange. Inhibition of PDK with dichloroacetate resulted in increased mitochondrial permeability and cell death in tozasertib‐resistant glioma cell lines. Based on these results, we believe that PDK is a selective target for the tozasertib resistance phenotype and should be considered for further preclinical evaluations. John Wiley and Sons Inc. 2021-06-23 2022-01 /pmc/articles/PMC8732347/ /pubmed/34058053 http://dx.doi.org/10.1002/1878-0261.13025 Text en © 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies 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 Jane, Esther P. Premkumar, Daniel R. Rajasundaram, Dhivyaa Thambireddy, Swetha Reslink, Matthew C. Agnihotri, Sameer Pollack, Ian F. Reversing tozasertib resistance in glioma through inhibition of pyruvate dehydrogenase kinases |
title | Reversing tozasertib resistance in glioma through inhibition of pyruvate dehydrogenase kinases |
title_full | Reversing tozasertib resistance in glioma through inhibition of pyruvate dehydrogenase kinases |
title_fullStr | Reversing tozasertib resistance in glioma through inhibition of pyruvate dehydrogenase kinases |
title_full_unstemmed | Reversing tozasertib resistance in glioma through inhibition of pyruvate dehydrogenase kinases |
title_short | Reversing tozasertib resistance in glioma through inhibition of pyruvate dehydrogenase kinases |
title_sort | reversing tozasertib resistance in glioma through inhibition of pyruvate dehydrogenase kinases |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8732347/ https://www.ncbi.nlm.nih.gov/pubmed/34058053 http://dx.doi.org/10.1002/1878-0261.13025 |
work_keys_str_mv | AT janeestherp reversingtozasertibresistanceingliomathroughinhibitionofpyruvatedehydrogenasekinases AT premkumardanielr reversingtozasertibresistanceingliomathroughinhibitionofpyruvatedehydrogenasekinases AT rajasundaramdhivyaa reversingtozasertibresistanceingliomathroughinhibitionofpyruvatedehydrogenasekinases AT thambireddyswetha reversingtozasertibresistanceingliomathroughinhibitionofpyruvatedehydrogenasekinases AT reslinkmatthewc reversingtozasertibresistanceingliomathroughinhibitionofpyruvatedehydrogenasekinases AT agnihotrisameer reversingtozasertibresistanceingliomathroughinhibitionofpyruvatedehydrogenasekinases AT pollackianf reversingtozasertibresistanceingliomathroughinhibitionofpyruvatedehydrogenasekinases |