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

• Published in: bioRxiv
• Main Authors: Dieguez-Martinez, Nora, Espinosa-Gil, Sergio, Yoldi, Guillermo, Megias-Roda, Elisabet, Idoia Bolinaga-Ayala Jr, Vinas-Casas, Maria, Domingo-Orti, Ines, Perez-Montoyo, Hector, Bayascas, Jose R, Colas, Eva, Dolcet, Xavier, Lizcano, Jose M
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 31.05.2022
• Subjects: Apoptosis; Cancer; Carboplatin; Cell growth; Cell proliferation; Cell survival; Chemotherapy; Cytokines; Endometrial cancer; Endometrium; Growth factors; Kinases; NF-κB protein; Oxidative stress; Paclitaxel; Patients; Radiation therapy; RelA protein; Signal transduction; Toxicity; Tumors; Xenografts
• DOI: 10.1101/2022.05.31.494135

Endometrial cancer (EC) is the most common type of gynaecologic 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 molecular therapies. The MEK5-ERK5 pathway is activated in response to growth factors and to different forms of stress, including oxidative stress and cytokines. Previous evidence support a role for the MEK5-ERK5 pathway in the pathology of several cancers. We have 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 decreased EGF-induced EC cell proliferation, and that depletion of MEK5 resulted in EC impaired proliferation and reduced tumor growth capacity in nude mice. Pharmacologic or genetic silencing of ERK5 impaired NF-κB 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, 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 depletion or NF-κB 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. Competing Interest Statement Elisabet Megias-Roda and Hector Perez-Montoyo are Ability Pharmaceuticals employees; Jose M Lizcano serves as an uncompensated member of Ability Pharmaceuticals advisory board, and holds shares of the company.