VDAC1 is a molecular target in glioblastoma, with its depletion leading to reprogrammed metabolism and reversed oncogenic properties.
BACKGROUND
Glioblastoma (GBM), an aggressive brain tumor with frequent relapses and a high mortality, still awaits an effective treatment. Like many cancers, GBM cells acquire oncogenic properties, including metabolic reprogramming, vital for growth. As such, tumor metabolism is an emerging avenue for cancer therapy. One relevant target is the voltage-dependent anion channel 1 (VDAC1), a mitochondrial protein controlling cell energy and metabolic homeostasis.


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.


CONCLUSIONS
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.
Department of Life Sciences, and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev,Beer-Sheva, Israel; Department of Pathology, Soroka University Medical Centre, and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Tasleem
T
Arif
Department of Life Sciences, and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev,Beer-Sheva, Israel; Department of Pathology, Soroka University Medical Centre, and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Yakov
Y
Krelin
Department of Life Sciences, and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev,Beer-Sheva, Israel; Department of Pathology, Soroka University Medical Centre, and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Itay
I
Nakdimon
Department of Life Sciences, and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev,Beer-Sheva, Israel; Department of Pathology, Soroka University Medical Centre, and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Daniel
D
Benharroch
Department of Life Sciences, and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev,Beer-Sheva, Israel; Department of Pathology, Soroka University Medical Centre, and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Avijit
A
Paul
Department of Life Sciences, and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev,Beer-Sheva, Israel; Department of Pathology, Soroka University Medical Centre, and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Daniela
D
Dadon-Klein
Department of Life Sciences, and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev,Beer-Sheva, Israel; Department of Pathology, Soroka University Medical Centre, and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Varda
V
Shoshan-Barmatz
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015870:Gene Expression; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D006801:Humans; D008297:Male; D008819:Mice, Nude; D034741:RNA, Small Interfering / Q000008:administration & dosage; D059467:Transcriptome; D050995:Voltage-Dependent Anion Channel 1 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D034741:RNA, Small Interfering; C494762:VDAC1 protein, human; D050995:Voltage-Dependent Anion Channel 1
glioblastoma; metabolism; mitochondria; siRNA; voltage-dependent anion channel