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The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival

Endometrial cancer (EC) is the most common type of gynecologic cancer in women of developed countries. Despite surgery combined with chemo-/radiotherapy regimens, overall survival of patients with high-risk EC tumors is poor, indicating a need for novel therapies. The MEK5-ERK5 pathway is activated...

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Autores principales: Diéguez-Martínez, Nora, Espinosa-Gil, Sergio, Yoldi, Guillermo, Megías-Roda, Elisabet, Bolinaga-Ayala, Idoia, Viñas-Casas, Maria, Gorgisen, Gokhan, Domingo-Ortí, Inés, Pérez-Montoyo, Héctor, Bayascas, Jose R., Colas, Eva, Dolcet, Xavier, Lizcano, Jose M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9485191/
https://www.ncbi.nlm.nih.gov/pubmed/36123565
http://dx.doi.org/10.1007/s00018-022-04541-6
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author Diéguez-Martínez, Nora
Espinosa-Gil, Sergio
Yoldi, Guillermo
Megías-Roda, Elisabet
Bolinaga-Ayala, Idoia
Viñas-Casas, Maria
Gorgisen, Gokhan
Domingo-Ortí, Inés
Pérez-Montoyo, Héctor
Bayascas, Jose R.
Colas, Eva
Dolcet, Xavier
Lizcano, Jose M.
author_facet Diéguez-Martínez, Nora
Espinosa-Gil, Sergio
Yoldi, Guillermo
Megías-Roda, Elisabet
Bolinaga-Ayala, Idoia
Viñas-Casas, Maria
Gorgisen, Gokhan
Domingo-Ortí, Inés
Pérez-Montoyo, Héctor
Bayascas, Jose R.
Colas, Eva
Dolcet, Xavier
Lizcano, Jose M.
author_sort Diéguez-Martínez, Nora
collection PubMed
description Endometrial cancer (EC) is the most common type of gynecologic cancer in women of developed countries. Despite surgery combined with chemo-/radiotherapy regimens, overall survival of patients with high-risk EC tumors is poor, indicating a need for novel therapies. The MEK5-ERK5 pathway is activated in response to growth factors and to different stressors, including oxidative stress and cytokines. Previous evidence supports a role for the MEK5-ERK5 pathway in the pathology of several cancers. We investigated the role of ERK5 in EC. In silico analysis of the PanCancer Atlas dataset showed alterations in components of the MEK5-ERK5 pathway in 48% of EC patients. Here, we show that ERK5 inhibition or silencing decreased EGF-induced EC cell proliferation, and that genetic deletion of MEK5 resulted in EC impaired proliferation and reduced tumor growth capacity in nude mice. Pharmacologic inhibition or ERK5 silencing impaired NF-kB pathway in EC cells and xenografts. Furthermore, we found a positive correlation between ERK5 and p65/RELA protein levels in human EC tumor samples. Mechanistically, genetic or pharmacologic impairment of ERK5 resulted in downregulation of NEMO/IKKγ expression, leading to impaired p65/RELA activity and to apoptosis in EC cells and xenografts, which was rescued by NEMO/IKKγ overexpression. Notably, ERK5 inhibition, MEK5 deletion or NF-kB inhibition sensitized EC cells to standard EC chemotherapy (paclitaxel/carboplatin) toxicity, whereas ERK5 inhibition synergized with paclitaxel to reduce tumor xenograft growth in mice. Together, our results suggest that the ERK5-NEMO-NF-κB pathway mediates EC cell proliferation and survival. We propose the ERK5/NF-κB axis as new target for EC treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-022-04541-6.
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spelling pubmed-94851912022-09-21 The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival Diéguez-Martínez, Nora Espinosa-Gil, Sergio Yoldi, Guillermo Megías-Roda, Elisabet Bolinaga-Ayala, Idoia Viñas-Casas, Maria Gorgisen, Gokhan Domingo-Ortí, Inés Pérez-Montoyo, Héctor Bayascas, Jose R. Colas, Eva Dolcet, Xavier Lizcano, Jose M. Cell Mol Life Sci Original Article Endometrial cancer (EC) is the most common type of gynecologic cancer in women of developed countries. Despite surgery combined with chemo-/radiotherapy regimens, overall survival of patients with high-risk EC tumors is poor, indicating a need for novel therapies. The MEK5-ERK5 pathway is activated in response to growth factors and to different stressors, including oxidative stress and cytokines. Previous evidence supports a role for the MEK5-ERK5 pathway in the pathology of several cancers. We investigated the role of ERK5 in EC. In silico analysis of the PanCancer Atlas dataset showed alterations in components of the MEK5-ERK5 pathway in 48% of EC patients. Here, we show that ERK5 inhibition or silencing decreased EGF-induced EC cell proliferation, and that genetic deletion of MEK5 resulted in EC impaired proliferation and reduced tumor growth capacity in nude mice. Pharmacologic inhibition or ERK5 silencing impaired NF-kB pathway in EC cells and xenografts. Furthermore, we found a positive correlation between ERK5 and p65/RELA protein levels in human EC tumor samples. Mechanistically, genetic or pharmacologic impairment of ERK5 resulted in downregulation of NEMO/IKKγ expression, leading to impaired p65/RELA activity and to apoptosis in EC cells and xenografts, which was rescued by NEMO/IKKγ overexpression. Notably, ERK5 inhibition, MEK5 deletion or NF-kB inhibition sensitized EC cells to standard EC chemotherapy (paclitaxel/carboplatin) toxicity, whereas ERK5 inhibition synergized with paclitaxel to reduce tumor xenograft growth in mice. Together, our results suggest that the ERK5-NEMO-NF-κB pathway mediates EC cell proliferation and survival. We propose the ERK5/NF-κB axis as new target for EC treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-022-04541-6. Springer International Publishing 2022-09-19 2022 /pmc/articles/PMC9485191/ /pubmed/36123565 http://dx.doi.org/10.1007/s00018-022-04541-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 Original Article
Diéguez-Martínez, Nora
Espinosa-Gil, Sergio
Yoldi, Guillermo
Megías-Roda, Elisabet
Bolinaga-Ayala, Idoia
Viñas-Casas, Maria
Gorgisen, Gokhan
Domingo-Ortí, Inés
Pérez-Montoyo, Héctor
Bayascas, Jose R.
Colas, Eva
Dolcet, Xavier
Lizcano, Jose M.
The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival
title The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival
title_full The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival
title_fullStr The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival
title_full_unstemmed The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival
title_short The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival
title_sort erk5/nf-κb signaling pathway targets endometrial cancer proliferation and survival
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9485191/
https://www.ncbi.nlm.nih.gov/pubmed/36123565
http://dx.doi.org/10.1007/s00018-022-04541-6
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