TY - JOUR
T1 - The ERK5/NF-κB signaling pathway targets endometrial cancer proliferation and survival
AU - Diéguez-Martínez, Nora
AU - Espinosa-Gil, Sergio
AU - Yoldi, Guillermo
AU - Megías-Roda, Elisabet
AU - Bolinaga-Ayala, Idoia
AU - Viñas-Casas, Maria
AU - Domingo-Ortí, Inés
AU - Pérez-Montoyo, Héctor
AU - Bayascas, Jose R.
AU - Colas, Eva
AU - Dolcet, Xavier
AU - Lizcano, Jose Miguel
N1 - Funding Information:
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).
Funding Information:
S. Espinosa-Gil is a recipient of a fellowship from FI-AGAUR (2020-FISDU-00575). N. Dieguez-Martinez and I. Bolinaga-Ayala are recipients of PIF fellowships from UAB. Gokhan Gorgisen is a recipient of the 2219 International Postdoctoral Research Fellowship Program for Turkish Citizens from the Scientific and Technological Research Council of Turkey (TUBİTAK). We are grateful to Cristina Gutierrez, and Neus Ontiveros for tissue culture, to Mar Hernández for IHC assistance. We also thank Miguel Segura and Victor Yuste for helpful discussions. We thank the following UAB Services: Servei de Cultius Cel·lulars INc, Laboratori de Luminiscència Espectroscopia and Servei Genòmica Informàtica. We also thank to the UAT Service from VHIR.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/9/19
Y1 - 2022/9/19
N2 - 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.
AB - 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.
KW - Anticancer drug
KW - Apoptosis
KW - ERK5
KW - Endometrial cancer
KW - Map kinase
KW - NF-kB
U2 - 10.1007/s00018-022-04541-6
DO - 10.1007/s00018-022-04541-6
M3 - Article
C2 - 36123565
AN - SCOPUS:85138141574
SN - 1420-682X
VL - 79
SP - 524
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
IS - 10
M1 - 524
ER -