RRC ID 54181
Author Chi KC, Tsai WC, Wu CL, Lin TY, Hueng DY.
Title An Adult Drosophila Glioma Model for Studying Pathometabolic Pathways of Gliomagenesis.
Journal Mol Neurobiol
Abstract Glioblastoma multiforme (GBM), the most prevalent brain tumor in adults, has extremely poor prognosis. Frequent genetic alterations that activate epidermal growth factor receptor (EGFR) and phosphatidylinositol-3 kinase (PI3K) signaling, as well as metabolic remodeling, have been associated with gliomagenesis. To establish a whole-animal approach that can be used to readily identify individual pathometabolic signaling factors, we induced glioma formation in the adult Drosophila brain by activating the EGFR-PI3K pathway. Glioma-induced animals showed significantly enlarged brain volume, early locomotor abnormalities, memory deficits, and a shorter lifespan. Combining bioinformatics analysis and glial-specific gene knockdown in the adult fly glioma model, we identified four evolutionarily conserved metabolic genes, including ALDOA, ACAT1, ELOVL6, and LOX, that were involved in gliomagenesis. Silencing of ACAT1, which controls cholesterol homeostasis, reduced brain enlargement and increased the lifespan of the glioma-bearing flies. In GBM patients, ACAT1 is overexpressed and correlates with poor survival outcomes. Moreover, pharmacological inhibition of ACAT1 in human glioma cell lines revealed that it is essential for tumor proliferation. Collectively, these results imply that ACAT1 is a potential therapeutic target, and cholesterol homeostasis is strongly related to glioma formation. This in vivo model provides several rapid and robust phenotypic readouts, allowing determination of the pathometabolic pathways involved in gliomagenesis, as well as providing valuable information for novel therapeutic strategies.
Volume 56(6)
Pages 4589-4599
Published 2019-6-1
DOI 10.1007/s12035-018-1392-2
PII 10.1007/s12035-018-1392-2
PMID 30357574
MeSH Aging / pathology* Animals Behavior, Animal Brain Neoplasms / genetics Brain Neoplasms / metabolism* Brain Neoplasms / pathology* Brain Neoplasms / physiopathology Carcinogenesis / metabolism* Cell Line, Tumor Cell Survival Disease Models, Animal Drosophila melanogaster / metabolism* Gene Expression Regulation, Neoplastic Glioma / genetics Glioma / metabolism* Glioma / pathology* Glioma / physiopathology Humans Longevity Memory Disorders / complications Memory Disorders / physiopathology Metabolic Networks and Pathways* Motor Activity Sterol O-Acyltransferase / metabolism Survival Analysis
IF 4.5
Times Cited 3
Drosophila 8112R-2