Journal Article

Etiopathogenic role of ERK5 signaling in sarcoma: prognostic and therapeutic implications

Pandiella, Atanasio, Sánchez-Fdez, Adrián, Del Carmen, Sofía, Ruíz-Hidalgo, Mª José, Abad, Mar, Jiménez-Suárez, Jaime, Arconada-Luque, Elena, Sánchez-Prieto, Ricardo, Matilla-Almazán, Sofía, Esparís-Ogando, Azucena, Chinchilla-Tábora, Luis Miguel

2023

Overview

Sarcomas constitute a heterogeneous group of rare and difficult-to-treat tumors that can affect people of all ages, representing one of the most common forms of cancer in childhood and adolescence. Little is known about the molecular entities involved in sarcomagenesis. Therefore, the identification of processes that lead to the development of the disease may uncover novel therapeutic opportunities. Here, we show that the MEK5/ERK5 signaling pathway plays a critical role in the pathogenesis of sarcomas. By developing a mouse model engineered to express a constitutively active form of MEK5, we demonstrate that the exclusive activation of the MEK5/ERK5 pathway can promote sarcomagenesis. Histopathological analyses identified these tumors as undifferentiated pleomorphic sarcomas. Bioinformatic studies revealed that sarcomas are the tumors in which ERK5 is most frequently amplified and overexpressed. Moreover, analysis of the impact of ERK5 protein expression on overall survival in patients diagnosed with different sarcoma types in our local hospital showed a 5-fold decrease in median survival in patients with elevated ERK5 expression compared with those with low expression. Pharmacological and genetic studies revealed that targeting the MEK5/ERK5 pathway drastically affects the proliferation of human sarcoma cells and tumor growth. Interestingly, sarcoma cells with knockout of ERK5 or MEK5 were unable to form tumors when engrafted into mice. Taken together, our results reveal a role of the MEK5/ERK5 pathway in sarcomagenesis and open a new scenario to be considered in the treatment of patients with sarcoma in which the ERK5 pathway is pathophysiologically involved. Cancer: Signaling pathway offers new drug target for sarcoma Therapies directed at a key signaling pathway could help reduce the growth of sarcomas, connective tissue cancers that affect fat, muscles, nerves and other tissues. Azucena Esparís-Ogando from the Instituto de Investigación Biomédica de Salamanca (IBSAL), Spain, and colleagues showed that in a genetically engineered mouse model the activation of the MEK5 enzyme activates the ERK5 enzyme, a regulator of genes involved in cell proliferation, differentiation and survival, and promotes the development of soft-tissue sarcomas. Drugs that block MEK5 or ERK5 activity reduced the growth of sarcoma cell lines and sarcoma tumors implanted into mice. A similar drug strategy could be applicable in cancer treatment in humans given the authors’ demonstration that ERK5 is frequently overexpressed in human sarcomas and that patients with elevated ERK5 have worse survival outcomes.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group,생화학분자생물학회
• Subject: 13/1 / 13/106 / 13/51 / 13/89 / 13/95 / 38/70 / 45/41 / 631/67/1059/602 / 631/67/1798 / 631/67/1857 / 631/67/70 / 64/110 / 692/308/575 / 82/80 / Animals / Biomedical and Life Sciences / Biomedicine / Cancer / Cell differentiation / Cell proliferation / Cell survival / Children / Connective tissues / Drug development / Enzymes / Genetic engineering / Humans / MAP Kinase Kinase 5 - genetics / MAP Kinase Kinase 5 - metabolism / MAP Kinase Signaling System / Medical Biochemistry / Mice / Molecular Medicine / Muscles / Nerves / Patients / Prognosis / Sarcoma / Sarcoma - genetics / Signal transduction / Stem Cells / Therapeutic targets / Tumor cell lines / Tumors / 생화학