Cargando…
Anti-cancer efficacy including Rb-deficient tumors and VHL-independent HIF1α proteasomal destabilization by dual targeting of CDK1 or CDK4/6 and HSP90
A prevalent characteristic of solid tumors is intra-tumoral hypoxia. Hypoxia-inducible factor 1α (HIF1α) predominantly mediates the adaptive response to O(2) oscillation and is linked to multiple malignant hallmarks. Here we describe a strategy to robustly target HIF1α by dual inhibition of CDK(s) a...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8536770/ https://www.ncbi.nlm.nih.gov/pubmed/34686682 http://dx.doi.org/10.1038/s41598-021-00150-8 |
_version_ | 1784588093294116864 |
---|---|
author | Zhao, Shuai Zhou, Lanlan Dicker, David T. Lev, Avital Zhang, Shengliang Ross, Eric El-Deiry, Wafik S. |
author_facet | Zhao, Shuai Zhou, Lanlan Dicker, David T. Lev, Avital Zhang, Shengliang Ross, Eric El-Deiry, Wafik S. |
author_sort | Zhao, Shuai |
collection | PubMed |
description | A prevalent characteristic of solid tumors is intra-tumoral hypoxia. Hypoxia-inducible factor 1α (HIF1α) predominantly mediates the adaptive response to O(2) oscillation and is linked to multiple malignant hallmarks. Here we describe a strategy to robustly target HIF1α by dual inhibition of CDK(s) and heat shock protein 90 (HSP90). We show that CDK1 may contribute to HSP90-mediated HIF1α stabilization. CDK1 knockdown enhances the decrease of HIF1α by HSP90 inhibition. Dual inhibition of CDK1 and HSP90 significantly increases apoptosis and synergistically inhibits cancer cell viability. Similarly, targeting CDK4/6 using FDA-approved inhibitors in combination with HSP90 inhibition shows a class effect on HIF1α inhibition and cancer cell viability suppression not only in colorectal but also in various other cancer types, including Rb-deficient cancer cells. Dual inhibition of CDK4/6 and HSP90 suppresses tumor growth in vivo. In summary, combined targeting of CDK(s) (CDK1 or CDK4/6) and HSP90 remarkably inhibits the expression level of HIF1α and shows promising anti-cancer efficacy with therapeutic potential. |
format | Online Article Text |
id | pubmed-8536770 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-85367702021-10-25 Anti-cancer efficacy including Rb-deficient tumors and VHL-independent HIF1α proteasomal destabilization by dual targeting of CDK1 or CDK4/6 and HSP90 Zhao, Shuai Zhou, Lanlan Dicker, David T. Lev, Avital Zhang, Shengliang Ross, Eric El-Deiry, Wafik S. Sci Rep Article A prevalent characteristic of solid tumors is intra-tumoral hypoxia. Hypoxia-inducible factor 1α (HIF1α) predominantly mediates the adaptive response to O(2) oscillation and is linked to multiple malignant hallmarks. Here we describe a strategy to robustly target HIF1α by dual inhibition of CDK(s) and heat shock protein 90 (HSP90). We show that CDK1 may contribute to HSP90-mediated HIF1α stabilization. CDK1 knockdown enhances the decrease of HIF1α by HSP90 inhibition. Dual inhibition of CDK1 and HSP90 significantly increases apoptosis and synergistically inhibits cancer cell viability. Similarly, targeting CDK4/6 using FDA-approved inhibitors in combination with HSP90 inhibition shows a class effect on HIF1α inhibition and cancer cell viability suppression not only in colorectal but also in various other cancer types, including Rb-deficient cancer cells. Dual inhibition of CDK4/6 and HSP90 suppresses tumor growth in vivo. In summary, combined targeting of CDK(s) (CDK1 or CDK4/6) and HSP90 remarkably inhibits the expression level of HIF1α and shows promising anti-cancer efficacy with therapeutic potential. Nature Publishing Group UK 2021-10-22 /pmc/articles/PMC8536770/ /pubmed/34686682 http://dx.doi.org/10.1038/s41598-021-00150-8 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Zhao, Shuai Zhou, Lanlan Dicker, David T. Lev, Avital Zhang, Shengliang Ross, Eric El-Deiry, Wafik S. Anti-cancer efficacy including Rb-deficient tumors and VHL-independent HIF1α proteasomal destabilization by dual targeting of CDK1 or CDK4/6 and HSP90 |
title | Anti-cancer efficacy including Rb-deficient tumors and VHL-independent HIF1α proteasomal destabilization by dual targeting of CDK1 or CDK4/6 and HSP90 |
title_full | Anti-cancer efficacy including Rb-deficient tumors and VHL-independent HIF1α proteasomal destabilization by dual targeting of CDK1 or CDK4/6 and HSP90 |
title_fullStr | Anti-cancer efficacy including Rb-deficient tumors and VHL-independent HIF1α proteasomal destabilization by dual targeting of CDK1 or CDK4/6 and HSP90 |
title_full_unstemmed | Anti-cancer efficacy including Rb-deficient tumors and VHL-independent HIF1α proteasomal destabilization by dual targeting of CDK1 or CDK4/6 and HSP90 |
title_short | Anti-cancer efficacy including Rb-deficient tumors and VHL-independent HIF1α proteasomal destabilization by dual targeting of CDK1 or CDK4/6 and HSP90 |
title_sort | anti-cancer efficacy including rb-deficient tumors and vhl-independent hif1α proteasomal destabilization by dual targeting of cdk1 or cdk4/6 and hsp90 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8536770/ https://www.ncbi.nlm.nih.gov/pubmed/34686682 http://dx.doi.org/10.1038/s41598-021-00150-8 |
work_keys_str_mv | AT zhaoshuai anticancerefficacyincludingrbdeficienttumorsandvhlindependenthif1aproteasomaldestabilizationbydualtargetingofcdk1orcdk46andhsp90 AT zhoulanlan anticancerefficacyincludingrbdeficienttumorsandvhlindependenthif1aproteasomaldestabilizationbydualtargetingofcdk1orcdk46andhsp90 AT dickerdavidt anticancerefficacyincludingrbdeficienttumorsandvhlindependenthif1aproteasomaldestabilizationbydualtargetingofcdk1orcdk46andhsp90 AT levavital anticancerefficacyincludingrbdeficienttumorsandvhlindependenthif1aproteasomaldestabilizationbydualtargetingofcdk1orcdk46andhsp90 AT zhangshengliang anticancerefficacyincludingrbdeficienttumorsandvhlindependenthif1aproteasomaldestabilizationbydualtargetingofcdk1orcdk46andhsp90 AT rosseric anticancerefficacyincludingrbdeficienttumorsandvhlindependenthif1aproteasomaldestabilizationbydualtargetingofcdk1orcdk46andhsp90 AT eldeirywafiks anticancerefficacyincludingrbdeficienttumorsandvhlindependenthif1aproteasomaldestabilizationbydualtargetingofcdk1orcdk46andhsp90 |