Title:
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The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival
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Author:
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Diéguez-Martínez, Nora; Espinosa-Gil, Sergio; Yoldi Salinas, Guillermo; Megías-Roda, Elisabet; Bolinaga-Ayala, Idoia; Viñas-Casas, Maria; Gorgisen, Gokhan; Domingo-Ortí, Inés; Pérez-Montoyo, Héctor; Bayascas Ramírez, José Ramón; Colás Ortega, Eva; Dolcet, Xavier; Lizcano de Vega, José Miguel
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Abstract:
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Altres ajuts: acords transformatius de la UAB |
Abstract:
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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 altera- tions 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 prolifera- tion and survival. We propose the ERK5/NF-κB axis as new target for EC treatment.The online version contains supplementary material available at 10.1007/s00018-022-04541-6 |
Subject(s):
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-Map kinase -ERK5 -NF-kB -Apoptosis -Endometrial cancer -Anticancer drug |
Rights:
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open access
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https://creativecommons.org/licenses/by/4.0/ |
Document type:
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Article |
Published by:
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Share:
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Uri:
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https://ddd.uab.cat/record/266010
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