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RAB38 Facilitates Energy Metabolism and Counteracts Cell Death in Glioblastoma Model Systems

ABSTRACT: Glioblastoma is a high-grade glial neoplasm with a patient survival of 12-18 months. Therefore, there is an urgent need for identification of novel therapeutic targets. RAB38 is a member of a family of small GTPase proteins and has been implicated in regulating cell proliferation and survival in tumors. The role of RAB38 in glioblastoma is unexplored. Here, we used human glioblastoma cell lines to test the hypothesis that RAB38 regulates glioblastoma growth. We found that genetic interference of RAB38 resulted in a marked decrease in glioblastoma growth, but not in astrocytes, through inhibition of proliferation and cell death induction accompanied by loss of mitochondrial membrane potential. Transcriptome analysis with subsequent gene set enrichment analysis (GSEA) showed that RAB38 silencing leads to changes in genes related to mitochondrial metabolism, intrinsic apoptosis (e.g. Bcl-xL) as well as a reduction in MYC targets. Consistently, rescue experiments demonstrated that loss of RAB38 causes reduction of glioblastoma viability through downregulation of both Bcl-xL and c-Myc, respectively. Moreover, RAB38 knock-down inhibited both glycolysis and oxidative phosphorylation. Consistently, interference with RAB38 enhanced cell death induced by BH3-mimetics. RAB38 antagonists are under development, but not yet clinically available. We found that FDA approved statins led to a rapid reduction in RAB38 protein expression, increased cell death and phenocopied some of the molecular changes elicited by loss of RAB38. In summary, our findings suggest that RAB38 is a potential therapeutic target for glioblastoma treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE162444 | GEO | 2021/06/21

REPOSITORIES: GEO

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