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Du F , Yuelling L , Lee EH , Wang Y , Liao S , Cheng Y , Zhang L , Zheng C , Peri S , Cai KQ , Ng JMY , Curran T , Li P , Yang ZJ
Leukotriene Synthesis Is Critical for Medulloblastoma Progression
Clin Cancer Res. 2019 Nov 1;25(21) :6475-6486
PMID: 31300449    PMCID: PMC6825543   
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Abstract
PURPOSE: Here, we examined the role of leukotrienes, well-known inflammatory mediators, in the tumorigenesis of hedgehog pathway-associated medulloblastoma, and tested the efficacies of antagonists of leukotriene biosynthesis in medulloblastoma treatment.Experimental Design: We examined the leukotriene levels in medulloblastoma cells by ELISA. We next tested whether leukotriene synthesis in medulloblastoma cells relied on activation of hedgehog pathway, or the presence of hedgehog ligand secreted by astrocytes. We then investigated whether leukotriene mediated hedgehog-induced Nestin expression in tumor cells. The functions of leukotriene in tumor cell proliferation and tumor growth in medulloblastoma were determined through knocking down 5-lipoxygenase (a critical enzyme for leukotriene synthesis) by shRNAs, or using 5-lipoxygenase-deficient mice. Finally, the efficacies of antagonists of leukotriene synthesis in medulloblastoma treatment were tested in vivo and in vitro. RESULTS: Leukotriene was significantly upregulated in medulloblastoma cells. Increased leukotriene synthesis relied on hedgehog ligand secreted by astrocytes, a major component of medulloblastoma microenvironment. Leukotriene stimulated tumor cells to express Nestin, a cytoskeletal protein essential for medulloblastoma growth. Genetic blockage of leukotriene synthesis dramatically suppressed medulloblastoma cell proliferation and tumor growth in vivo. Pharmaceutical inhibition of leukotriene synthesis markedly repressed medulloblastoma cell proliferation, but had no effect on proliferation of normal neuronal progenitors. Moreover, antagonists of leukotriene synthesis exhibited promising tumor inhibitory efficacies on drug-resistant medulloblastoma. CONCLUSIONS: Our findings reveal a novel signaling pathway that is critical for medulloblastoma cell proliferation and tumor progression, and that leukotriene biosynthesis represents a promising therapeutic target for medulloblastoma treatment.
Notes
Du, Fang Yuelling, Larra Lee, Eric H Wang, Yuan Liao, Shengyou Cheng, Yan Zhang, Li Zheng, Chaonan Peri, Suraj Cai, Kathy Q Ng, Jessica M Y Curran, Tom Li, Peng Yang, Zeng-Jie R01 CA178380/CA/NCI NIH HHS/United States R21 CA185504/CA/NCI NIH HHS/United States Journal Article United States Clin Cancer Res. 2019 Nov 1;25(21):6475-6486. doi: 10.1158/1078-0432.CCR-18-3549. Epub 2019 Jul 12.