2026-04-17T15:58:27Zhttps://recercat.cat/oai/request

oai:recercat.cat:10459.1/842562024-12-05T22:00:06Zcom_2072_3622col_2072_479130

The ERK5/NF‑κB signaling pathway targets endometrial cancer proliferation and survival Diéguez‑Martínez, Nora Espinosa‑Gil, Sergio Yoldi, Guillermo Gorgisen, Gokhan Domingo Ortí, Inés Viñas Casas, Maria Bolinaga Ayala, Idoia Megías Roda, Elisabet Pérez‑Montoyo, Héctor José Ramón, Bayascas Ramírez Colás, Eva Dolcet Roca, Xavier Lizcano, José M. Map kinase ERK5 NF-kB Apoptosis Endometrial cancer 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. Open Access Funding provided by Universitat Autonoma de Barcelona. The JM Lizcano research group was supported by grants from the Spanish Ministry of Economy and Competitiveness (MINECO, grant SAF2015-64237-R), and the Spanish Ministry of Science and Innovation (grant PID2019-107561RB-I00), and co-funded by the European Regional Development Fund (ERDF). 2022-11-19T14:57:50Z 2022-11-19T14:57:50Z 2022 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion https://doi.org/10.1007/s00018-022-04541-6 1420-682X http://hdl.handle.net/10459.1/84256 http://hdl.handle.net/10459.1/84256 eng info:eu-repo/grantAgreement/MINECO//SAF2015-64237-R/ES/DESARROLLO DE NUEVAS HERRAMIENTAS FARMACOLOGICAS ANTITUMORALES QUE DIRIJAN SU ACCION AL SILENCIAMIENTO O A LA INHIBICION DE LA MAP KINASA ERK5/ info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-107561RB-I00/ES/NUEVAS TERAPIAS ANTICANCER BASADAS EN LA MODULACION DE LA MAP KINASA ERK5/ Reproducció del document publicat a https://doi.org/10.1007/s00018-022-04541-6 Cellular and Molecular Life Sciences, 2022, vol. 79, art. 524. cc-by (c) Nora Diéguez Martínez et. al., 2022 info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/4.0/ Springer Science