Oncotarget

Research Papers:

Mitochondrial VDAC1-based peptides: Attacking oncogenic properties in glioblastoma

Anna Shteinfer-Kuzmine, Tasleem Arif, Yakov Krelin, Shambhoo Sharan Tripathi, Avijit Paul and Varda Shoshan-Barmatz _

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Oncotarget. 2017; 8:31329-31346. https://doi.org/10.18632/oncotarget.15455

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Abstract

Anna Shteinfer-Kuzmine1,*, Tasleem Arif1,*, Yakov Krelin1, Shambhoo Sharan Tripathi1, Avijit Paul1 and Varda Shoshan-Barmatz1

1Department of Life Sciences and the National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel

*First co-authors

Correspondence to:

Varda Shoshan-Barmatz, email: vardasb@bgu.ac.il

Keywords: apoptosis, glioblastoma, mitochondria, peptides, VDAC1

Received: June 29, 2016    Accepted: November 21, 2016    Published: February 17, 2017

ABSTRACT

Glioblastoma multiforme (GBM), a primary brain malignancy characterized by high morbidity, invasiveness, proliferation, relapse and mortality, is resistant to chemo- and radiotherapies and lacks effective treatment. GBM tumors undergo metabolic reprograming and develop anti-apoptotic defenses. We targeted GBM with a peptide derived from the mitochondrial protein voltage-dependent anion channel 1 (VDAC1), a key component of cell energy, metabolism and apoptosis regulation. VDAC1-based cell-penetrating peptides perturbed cell energy and metabolic homeostasis and induced apoptosis in several GBM and GBM-derived stem cell lines. We found that the peptides simultaneously attacked several oncogenic properties of human U-87MG cells introduced into sub-cutaneous xenograft mouse model, inhibiting tumor growth, invasion, and cellular metabolism, stemness and inducing apoptosis. Peptide-treated tumors showed decreased expression of all tested metabolism-related enzymes and transporters, and elevated levels of apoptotic proteins, such as p53, cytochrome c and caspases. Retro-Tf-D-LP4, containing the human transferrin receptor (TfR)-recognition sequence, crossed the blood-brain barrier (BBB) via the TfR that is highly expressed in the BBB to strongly inhibit tumor growth in an intracranial xenograft mouse model. In summary, the VDAC1-based peptides tested here offer a potentially affordable and innovative new conceptual therapeutic paradigm that might overcome GBM stemness and invasiveness and reduce relapse rates.


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