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Journal of Cancer Research and Clinical Oncology

Erschienen in:

17.06.2022 | Original Article – Cancer Research

Aberrant MEK5 signalling promotes clear cell renal cell carcinoma development via mTOR activation

verfasst von: Fangzhou Li, Xufeng Peng, Jiale Zhou, Qi Chen, Yonghui Chen

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 12/2022

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Abstract

Purpose

This study was designed to evaluate the role and expression of MEK5 signalling in clear cell renal cell carcinoma (ccRCC) and to determine the relevance of MEK5 and mTOR signalling in ccRCC.

Methods

The expression of MEK5 was compared between ccRCC and normal tissues using the ONCOMINE and TCGA databases. MEK5 expression was evaluated in 14 human ccRCC samples. CCK8, wound-healing, and clone formation assays were performed to examine the cell proliferation, migration, and clone formation abilities of ccRCC cells treated with MEK5 and the inhibitor BIX02189. Furthermore, Western blotting was performed to verify the regulation and influence of MEK5 on the mTOR signalling pathway. Finally, a murine subcutaneous tumour model was constructed, and the effect and safety of BIX02189 were evaluated in vivo.

Results

The ONCOMINE and TCGA databases indicated that MEK5 expression in ccRCC was significantly higher than that in normal tissues, which was further confirmed in clinical specimens. MEK5 knockdown markedly inhibited ccRCC cell proliferation, colony formation, and migration, whereas MEK5 overexpression resulted in the opposite results. Western blotting revealed that overexpression of MEK5 could further activate the mTOR signalling pathway. Moreover, the MEK5 inhibitor BIX02189 significantly inhibited cell proliferation, arrested the cell cycle in the G0/G1 phase, induced apoptosis, and effectively inhibited cell migration and clone formation. BIX02189 also showed an excellent antitumor effect and a favourable safety profile in murine models.

Conclusions

MEK5 expression was aberrantly increased in ccRCC, which activated the mTOR signalling pathway and regulated cell proliferation, cell cycle progression, migration, and clone formation in ccRCC. Targeted inhibition of MEK5 represents a promising new strategy in patients with ccRCC.

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Titel: Aberrant MEK5 signalling promotes clear cell renal cell carcinoma development via mTOR activation
verfasst von: Fangzhou Li
Xufeng Peng
Jiale Zhou
Qi Chen
Yonghui Chen
Publikationsdatum: 17.06.2022
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 12/2022
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-022-04058-2

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Aberrant MEK5 signalling promotes clear cell renal cell carcinoma development via mTOR activation