Abstract | BACKGROUND: METHODS: We used VDAC1-specific short interfering (si) RNA (si-VDAC1) to treat GBM cell lines and subcutaneous or intracranial-orthotopic GBM xenograft mouse models. Tumors were monitored using MRI, immunohistochemistry, immunoblotting, immunofluorescence, quantitative real-time PCR, transcription factor expression, and DNA microarray analyses. RESULTS: Silencing VDAC1 expression using si-VDAC1 in 9 glioblastoma-related cell lines, including patient-derived cells, led to marked decreases in VDAC1 levels and cell growth. Using si-VDAC1 in subcutaneous or intracranial-orthotopic GBM models inhibited tumor growth and reversed oncogenic properties, such as reprogrammed metabolism, stemness, angiogenesis, epithelial-mesenchymal transition, and invasiveness. In cells in culture, si-VDAC1 inhibits cancer neurosphere formation and, in tumors, targeted cancer stem cells, leading to their differentiation into neuronal-like cells. These VDAC1 depletion-mediated effects involved alterations in transcription factors regulating signaling pathways associated with cancer hallmarks. CONCLUSION: VDAC1 offers a target for GBM treatment, allowing for attacks on the interplay between metabolism and oncogenic signaling networks, leading to tumor cell differentiation into neuron- and astrocyte-like cells. Simultaneously attacking all of these processes, VDAC1 depletion overcame GBM heterogeneity and can replace several anticancer drugs that separately target angiogenesis, proliferation, or metabolism.
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Authors | Tasleem Arif, Yakov Krelin, Itay Nakdimon, Daniel Benharroch, Avijit Paul, Daniela Dadon-Klein, Varda Shoshan-Barmatz |
Journal | Neuro-oncology
(Neuro Oncol)
Vol. 19
Issue 7
Pg. 951-964
(Jul 01 2017)
ISSN: 1523-5866 [Electronic] England |
PMID | 28339833
(Publication Type: Journal Article)
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Copyright | © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected] |
Chemical References |
- RNA, Small Interfering
- VDAC1 protein, human
- Voltage-Dependent Anion Channel 1
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Topics |
- Animals
- Brain Neoplasms
(genetics, metabolism, therapy)
- Cell Line, Tumor
- Cell Proliferation
- Gene Expression
- Glioblastoma
(genetics, metabolism, therapy)
- Humans
- Male
- Mice, Nude
- RNA, Small Interfering
(administration & dosage)
- Transcriptome
- Voltage-Dependent Anion Channel 1
(antagonists & inhibitors)
- Xenograft Model Antitumor Assays
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