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Myeloid ERK5 deficiency suppresses tumor growth by blocking protumor macrophage
polarization via STAT3 inhibition
#MMPMID29507229
Giurisato E
; Xu Q
; Lonardi S
; Telfer B
; Russo I
; Pearson A
; Finegan KG
; Wang W
; Wang J
; Gray NS
; Vermi W
; Xia Z
; Tournier C
Proc Natl Acad Sci U S A
2018[Mar]; 115
(12
): E2801-E2810
PMID29507229
show ga
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.
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