LXA4 enhances prostate cancer progression by facilitating M2 macrophage polarization via inhibition of METTL3

•m6A modification in TAMs was associated with prostate cancer progression.•METTL3 impairs polarization of M2-like macrophages by inhibiting STAT6 activation.•LXA4 facilitated macrophage polarization toward an M2-like phenotype by inhibiting METTL3. Tumor-associated macrophages (TAMs) are major innat...

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Veröffentlicht in:International immunopharmacology 2022-06, Vol.107, p.108586-108586, Article 108586
Hauptverfasser: Jia, Gaozhen, Wang, Xingjie, Wu, Wenbo, Zhang, Yu, Chen, Shaoan, Zhao, Jing, Zhao, Wei, Li, Weiguo, Sun, Xiaowen, Han, Bangmin
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Sprache:eng
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Zusammenfassung:•m6A modification in TAMs was associated with prostate cancer progression.•METTL3 impairs polarization of M2-like macrophages by inhibiting STAT6 activation.•LXA4 facilitated macrophage polarization toward an M2-like phenotype by inhibiting METTL3. Tumor-associated macrophages (TAMs) are major innate immune cells that play crucial roles in prostate cancer onset and progression. Recently, increasing evidence has suggested that elevated N6-adenine methylation of mRNA is observed in prostate cancer tissues and is closely associated with a poor prognosis. However, its role in prostate cancer-associated macrophages remains poorly understood. Here, we showed that downregulation of METTL3 in prostate cancer TAMs modulated macrophages toward an M2-like phenotype and that this modulation was mediated by activation of STAT6. In addition, our data demonstrated that prostate cancer cell-derived small lipid molecule lipoxin A4 (LXA4) activated STAT6 by inhibiting METTL3. Treatment with PBP10 (an inhibitor of the LXA4 receptor) abolished the inhibition of METTL3 by LXA4 and consequently reduced the tumorigenicity of prostate cancer cells. Altogether, this work demonstrated that prostate cancer cells facilitate polarization of M2 like macrophages by releasing LXA4 via inhibiting METTL3. These findings provide new insight into the mechanism of microenvironmental regulation of macrophage polarization during prostate cancer progression.
ISSN:1567-5769
1878-1705
DOI:10.1016/j.intimp.2022.108586