Endometrial cancer is the most common type of gynecological cancer and is the fourth most common type of tumor in women in developed countries. Although it has a good prognosis if detected early, advanced and aggressive cases have a high mortality rate and are often resistant to standard chemotherapy treatments. Now, a study published in the journal Cellular and Molecular Life Sciences identified a new therapeutic strategy to tackle endometrial cancer (ENCA), based on inhibition of the MAPK kinase ERK5. Pharmacological blockade of ERK5 not only impairs proliferation and survival of ENCA cells, but also potentiates the anticancer activity of standard chemodrugs. In recent years, the ERK5 protein has shown to play a role in the development of several types of solid cancers. Scientists observed that up to 48% of patients with endometrial cancer show alterations in components of the ERK5 signaling pathway, which correlate with lower overall survival and reduced progression-free survival.
ERK5 is activated by direct phosphorylation of the kinase domain by the upstream kinase MEK5. Upon activation of the pathway, MEK5 phosphorylates cytosolic ERK5 to drive its translocation to the nucleus, where it acts as a transcriptional activator. Thereby, ERK5 has been reported to promote cell proliferation and cell cycle progression, among others. There are increasing evidence showing that ERK5 plays an important role in cancer cell proliferation and survival. Curiously, this kinase can also be activated by cyclic AMP, a notorious second messenger that has always been linked to inhibition of cellular proliferation and induction of diffferentiation. Cyclic AMP-induced cellular proliferation of cancer cell lineages, however, was often noted in lab experiments while scientists remaining perplexed by it. Almost 20 years ago, instead, it was discovered that a previoulsy unknown cAMP effector protein called Epac-1 could directly reach the MEK5-ERK5 signaling cascade.
The study has been led by researchers from the Protein Kinases in Cancer Research group at the Vall d’Hebron Research Institute (VHIR), the Department of Biochemistry and Molecular Biology of the Universitat Autònoma de Barcelona (UAB) and the UAB Institute of Neurosciences (INc-UAB), in collaboration with the Biomedical Research in Gynecology group of VHIR and the Oncological Pathology research group at Institute of Biomedical Research of Lleida (IRBLleida). In this work, carried out using cellular and mouse models, the researchers used a new ERK5 inhibitor (JWG-071), currently in preclinical development. JWG-071 is the first oral and selective ERK5 inhibitor that has shown antitumor activity and safety in animal models. They observed that inhibition of ERK5 reduces the proliferation of tumor cells, and it impairs the growth of tumors in animal models. This effect is mediated through NF-κB, a transcription factor that regulates the proliferation and survival of different tumor types, including endometrial cancer.
In a previous work publishd one year ago, the team also found that ERK5 inhibition in cancer cells promotes their death through a cellular reaction called ER-stress that lead to autophagy, or the cellular-autodigestion. Specifically, ERK5 inhibitors induced expression of the endoplasmic reticulum chaperone Grp78 (a hallmark of ER stress), the transcription regulators CHOP and ATF4, and the spliced form of XBP1 that controls the nuclear import of proteins. Pharmacological inhibition of endoplasmic protein stress response with the chemical chaperone TUDC, or ATF4 gene silencing, resulted in impaired cytotoxicity and autophagy induced by ERK blockade. Experimental data could also demonstrate that classical autophagy signaling proteins like mTORC and AMPK were not involved in the effects of ERK5 inhibitors. ON the other side, ERK inhibitors did synergize with brefeldin A, a chemical inhibitor of endoplasmic reticulum protein trafficking, resulting in a greater autophagic effect.
In analogy, since ERK5 inhibition potentiates the efficacy of chemotherapy used against ENCA cells (paclitaxel and carboplatin) in animal models, researchers believe that ERK5 could be an effective target to tackle endometrial cancer.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Diéguez-Martínez N et al. Cell Mol Life Sci 2022; 79(10):524.
Gámez-García A et al. Front Cell Dev Biol. 2021; 9:742049.
Erazo T, Espinoza-Gil S et al. Int J Mol Sci. 2020; 21(6):2203.
Dott. Gianfrancesco Cormaci
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