The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival
Diéguez-Martínez, Nora (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Espinosa-Gil, Sergio (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Yoldi Salinas, Guillermo (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Megías-Roda, Elisabet (Hospital Universitari Vall d'Hebron)
Bolinaga-Ayala, Idoia (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Viñas-Casas, Maria (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Gorgisen, Gokhan (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Domingo-Ortí, Inés (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Pérez-Montoyo, Héctor (Ability Pharmaceuticals)
Bayascas Ramírez, José Ramón (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Colás Ortega, Eva (Hospital Universitari Vall d'Hebron)
Dolcet, Xavier (Universitat de Lleida)
Lizcano de Vega, José Miguel (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Data:	2022
Resum:	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.
Ajuts:	Ministerio de Economía y Competitividad SAF2015-64237-R Agencia Estatal de Investigación PID2019-107561RB-I00 Agència de Gestió d'Ajuts Universitaris i de Recerca 2020-FISDU-00575
Nota:	Altres ajuts: acords transformatius de la UAB
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Map kinase ; ERK5 ; NF-kB ; Apoptosis ; Endometrial cancer ; Anticancer drug
Publicat a:	Cellular and molecular life sciences, Vol. 79 (2022) , p. 524, ISSN 1420-9071

DOI: 10.1007/s00018-022-04541-6
PMID: 36123565

20 p, 10.3 MB

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