Leukotriene Synthesis Is Critical for Medulloblastoma Progression.

Document Type

Article

Publication Date

11-1-2019

Identifier

DOI: 10.1158/1078-0432.CCR-18-3549; PMCID: PMC6825543

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.

Journal Title

Clinical cancer research : an official journal of the American Association for Cancer Research

Volume

25

Issue

21

First Page

6475

Last Page

6486

MeSH Keywords

Animals; Arachidonate 5-Lipoxygenase; Astrocytes; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Disease Progression; Gene Expression Regulation, Neoplastic; Hedgehog Proteins; Humans; Leukotrienes; Medulloblastoma; Mice; Mice, Knockout; RNA, Small Interfering; Signal Transduction

Keywords

Animals; Arachidonate 5-Lipoxygenase; Astrocytes; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Disease Progression; Gene Expression Regulation, Neoplastic; Hedgehog Proteins; Humans; Leukotrienes; Medulloblastoma; Mice; Mice, Knockout; RNA, Small Interfering; Signal Transduction

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