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

Abstract

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.

Bioinformatic analysis of differentially expressed profiles of lncRNAs and miRNAs with their related ceRNA network in endometrial cancer

“…[ 22 ] EGFR tyrosine kinase inhibitor is a small molecule EGFR inhibitor that can inhibit tyrosine kinase activation, block the EGFR signaling pathway, inhibit the proliferation and metastasis of tumor cells, and promote apoptosis through competitive endogenous ligand binding to EFGR. [ 23 ] Therefore, lncRNA may regulate the occurrence and development of tumors by regulating the expression of target genes by participating in the functional and signaling pathways listed above.…”

Modulation of ERK5 Activity as a Therapeutic Anti-Cancer Strategy

“…A range of studies involving genetic perturbation of ERK5 with siRNA/shRNA-mediated gene silencing or deletion of the MAPK7 gene (encoding ERK5) suggests that ERK5 signaling has a role in driving several distinct cellular phenotypes. Gene silencing of ERK5 has been shown to be antiproliferative in vitro or in vivo in a number of cancer cell types, including endometrial cancer, nonsmall cell lung cancer (NSCLC), small cell lung cancer (SCLC), melanoma, triple-negative breast cancer, and cholangiocarcinoma . In SCLC, a reduction in tumor cell proliferation upon ERK5 shRNA knockdown was not rescued by kinase-dead ERK5, in contrast to wild-type ERK5, suggesting that ERK5 kinase activity is important in mediating proliferation in this tumor type .…”

“…JWG-071 exhibits greatly (>10-fold) improved selectivity for ERK5 over BRD4 in comparison to XMD8-92 but retains much of XMD8-92’s potency toward other kinases including LRRK2, DCAMKL1, and PLK4. , The improved selectivity over BRD4 has been attributed to steric clash of the sec -butyl group with the αC-helix of BRD4. Interestingly, JWG-071 has demonstrated tumor-suppressive activity in endometrial cancer xenografts with intraperitoneal administration …”

MAP kinase ERK5 modulates cancer cell sensitivity to extrinsic apoptosis induced by death-receptor agonists and Natural Killer cells

“…Therefore, MEK5 knockout cells lack ERK5 kinase activity. We recently reported that MEK5-KO Ishikawa cells, while lacking ERK5 activity, show normal activation of other MAP kinases (ERK1/2, p38s or JNKs), or components of the PI3K pathway (Akt, mTORC1 or p70S6K) in response to mitogens, stressors or insulin 20 . On the other hand, ERK5-KO cells lack both kinase activity-dependent and -independent functions.…”