VDAC1-Based Peptides as Potential Modulators of VDAC1 Interactions with Its Partners and as a Therapeutic for Cancer,
Anna Shteinfer-Kuzmine1, Manikandan Santhanam2, Varda Shoshan-Barmatz1,2
1National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
Abstract:
This review presents current knowledge related to the voltage-dependent anion channel-1 (VDAC1) as a multi-functional mitochondrial protein that acts in regulating both cell life and death. The location of VDAC1 at the outer mitochondrial membrane (OMM) allows control of metabolic cross-talk between the mitochondria and the rest of the cell, and also enables its interaction with proteins that are involved in metabolic, cell death, and survival pathways. VDAC1's interactions with over 150 proteins can mediate and regulate the integration of mitochondrial functions with cellular activities. To target these protein-protein interactions, VDAC1-derived peptides have been developed. This review focuses specifically on cell-penetrating VDAC1-based peptides that were developed and used as a "decoy" to compete with VDAC1 for its VDAC1-interacting proteins. These peptides interfere with VDAC1 interactions, for example, with metabolism-associated proteins such as hexokinase (HK), or with anti-apoptotic proteins such as Bcl-2 and Bcl-xL. These and other VDAC1-interacting proteins are highly expressed in many cancers. The VDAC1-based peptides in cells in culture selectively affect cancerous, but not non-cancerous cells, inducing cell death in a variety of cancers, regardless of the cancer origin or genetics. They inhibit cell energy production, eliminate cancer stem cells, and act very rapidly and at low micro-molar concentrations. The activity of these peptides has been validated in several mouse cancer models of glioblastoma, lung, and breast cancers. Their anti-cancer activity involves a multi-pronged attack targeting the hallmarks of cancer. They were also found to be effective in treating non-alcoholic fatty liver disease and diabetes mellitus. Thus, VDAC1-based peptides, by targeting VDAC1-interacting proteins, offer an affordable and innovative new conceptual therapeutic paradigm that can potentially overcome heterogeneity, chemoresistance, and invasive metastatic formation.
Insights
Voltage-dependent anion channel-1 (VDAC1) peptides target cancer by disrupting VDAC1 interactions. These cell-penetrating peptides selectively kill cancer cells, offering a novel therapeutic approach for various cancers and metabolic diseases.
Area of Science:
- Mitochondrial biology
- Cancer therapeutics
- Metabolic diseases
Background:
- Voltage-dependent anion channel-1 (VDAC1) is a crucial mitochondrial protein regulating cell life and death.
- VDAC1's location on the outer mitochondrial membrane facilitates metabolic crosstalk and interactions with over 150 proteins involved in cellular pathways.
- Dysregulation of VDAC1 and its interacting proteins is implicated in various cancers and metabolic disorders.
Purpose of the Study:
- To review the development and application of VDAC1-derived peptides as targeted therapeutics.
- To highlight the mechanism of action of VDAC1-based peptides as decoys for VDAC1-interacting proteins.
- To assess the therapeutic potential of these peptides in cancer and metabolic diseases.
Main Methods:
- Development of cell-penetrating VDAC1-based peptides designed to compete with VDAC1 for protein binding.
- In vitro studies assessing the selectivity and efficacy of peptides against cancer cell lines.
- In vivo validation in mouse models of glioblastoma, lung, and breast cancers, as well as models for non-alcoholic fatty liver disease and diabetes mellitus.
Main Results:
- VDAC1-based peptides selectively induce cell death in various cancer types, irrespective of origin or genetics, at low concentrations.
- Peptides inhibit cancer cell energy production, eliminate cancer stem cells, and demonstrate rapid anti-cancer activity.
- Therapeutic efficacy was confirmed in multiple cancer models and in models of non-alcoholic fatty liver disease and diabetes mellitus.
Conclusions:
- VDAC1-based peptides represent a novel therapeutic strategy targeting VDAC1-interacting proteins.
- These peptides offer a potential solution to overcome cancer heterogeneity, chemoresistance, and metastasis.
- The findings suggest a promising, affordable, and innovative therapeutic paradigm for cancer and metabolic diseases.
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