Giurisato, E, Xu, Q, Lonardi, S, Telfer, B, Russo, I ORCID: https://orcid.org/0000-0002-2269-7078, Pearson, A, Finegan, K, Wang, W, Wang, J, Gray, N, Vermi, W, Xia, Z and Tournier, C (2018) Myeloid ERK5 deficiency suppresses tumor growth by blocking protumor macrophage polarization via STAT3 inhibition. Proceedings of the National Academy of Sciences, 115 (12). E2801 - E2810.

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Abstract

Owing to the prevalence of tumor-associated macrophages (TAMs) in cancer and their unique influence upon disease progression and malignancy, macrophage-targeted interventions have attracted notable attention in cancer immunotherapy. However, tractable targets to reduce TAM activities remain very few and far between because the signaling mechanisms underpinning protumor macrophage phenotypes are largely unknown. Here, we have investigated the role of the extracellular-regulated protein kinase 5 (ERK5) as a determinant of macrophage polarity. We report that the growth of carcinoma grafts was halted in myeloid ERK5-deficient mice. Coincidentally, targeting ERK5 in macrophages induced a transcriptional switch in favor of proinflammatory mediators. Further molecular analyses demonstrated that activation of the signal transducer and activator of transcription 3 (STAT3) via Tyr705 phosphorylation was impaired in erk5-deleted TAMs. Our study thus suggests that blocking ERK5 constitutes a treatment strategy to reprogram macrophages toward an antitumor state by inhibiting STAT3-induced gene expression.

Item Type: Article
Additional Information: Copyright © 2018 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Uncontrolled Keywords: ERK5; MAPK; STAT3; macrophages; tumors
Subjects: Q Science > QH Natural history
Q Science > QH Natural history > QH301 Biology
Divisions: Faculty of Natural Sciences > School of Life Sciences
Depositing User: Symplectic
Date Deposited: 09 Apr 2019 10:47
Last Modified: 15 Apr 2019 15:19
URI: http://eprints.keele.ac.uk/id/eprint/6168

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