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Subcellular Fractionation for ERK Activation Upon Mitochondrial-derived Peptide Treatment
Published on: September 25, 2017
Mitochondrial Voltage-Dependent Anion Channel 1-Hexokinase-II Complex-Targeted Strategy for Melanoma Inhibition Using
Fan Zhang1, Angelina Angelova2, Vasil M Garamus3
1Shanghai Key Laboratory of Functional Materials Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, P. R. China.
Abstract:
Targeted therapies of melanoma are of urgent need considering the resistance of this aggressive type of cancer to chemotherapeutics. The voltage-dependent anion channel 1 (VDAC1)-hexokinase-II (HK-II) complex is an emerging target for novel anticancer therapies based on induced mitochondria-mediated apoptosis. The low cell membrane permeability of the anticancer 12-mer peptide N-Ter (RDVFTKGYGFGL) derived from the N-terminal fragment of the VDAC1 protein impedes the intracellular targeting. Here, novel multiblock VDAC1-derived cationic amphiphilic peptides (referred to as Pal-N-Ter-TAT, pFL-N-Ter-TAT, and Pal-pFL-N-Ter-TAT) are designed with a self-assembly propensity and cell-penetrating properties. The created multiblock amphiphilic peptides of partial α-helical conformations form nanoparticles of ellipsoid-like shapes and are characterized by enhanced cellular uptake. The amphiphilic peptides can target mitochondria and dissociate the VDAC1-HK-II complex at the outer mitochondrial membrane, which result in mitochondria-mediated apoptosis. The latter is associated with decrease of the mitochondrial membrane potential, cytochrome c release, and changes of the expression levels of the apoptotic proteins in A375 melanoma cells. Importantly, the mitochondrial VDAC1-derived amphiphilic peptides have a comparable IC50 value for melanoma cells to a small-molecule drug, sorafenib, which has been previously used in clinical trials for melanoma. These results demonstrate the potential of the designed peptide constructs for efficient melanoma inhibition.
Insights
Novel peptide nanoparticles effectively target melanoma cells by disrupting the VDAC1-HK-II complex, inducing apoptosis. These VDAC1-derived peptides show promise as targeted melanoma therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Nanotechnology
Background:
- Melanoma exhibits resistance to conventional chemotherapy, necessitating novel therapeutic strategies.
- The voltage-dependent anion channel 1 (VDAC1)-hexokinase-II (HK-II) complex is a promising target for inducing mitochondria-mediated apoptosis in cancer cells.
- Previous VDAC1-derived peptides faced challenges with cell membrane permeability, limiting their therapeutic efficacy.
Purpose of the Study:
- To design and synthesize novel multiblock VDAC1-derived cationic amphiphilic peptides with enhanced cell-penetrating properties.
- To investigate the self-assembly, nanoparticle formation, and mitochondrial targeting capabilities of these novel peptides.
- To evaluate the therapeutic potential of these peptide constructs in inhibiting melanoma cell growth through mitochondria-mediated apoptosis.
Main Methods:
- Design and synthesis of multiblock VDAC1-derived cationic amphiphilic peptides (Pal-N-Ter-TAT, pFL-N-Ter-TAT, Pal-pFL-N-Ter-TAT).
- Characterization of peptide self-assembly, nanoparticle formation, and cellular uptake in A375 melanoma cells.
- Assessment of mitochondrial targeting, VDAC1-HK-II complex dissociation, and induction of apoptosis, including measurements of mitochondrial membrane potential, cytochrome c release, and apoptotic protein expression.
Main Results:
- The designed amphiphilic peptides self-assembled into ellipsoid-shaped nanoparticles with enhanced cellular uptake.
- These peptides successfully targeted mitochondria, dissociated the VDAC1-HK-II complex, and induced mitochondria-mediated apoptosis in melanoma cells.
- The peptides demonstrated a comparable IC50 value to sorafenib in inhibiting A375 melanoma cells, indicating significant therapeutic potential.
Conclusions:
- Novel VDAC1-derived amphiphilic peptides can form nanoparticles that efficiently target melanoma mitochondria.
- Dissociation of the VDAC1-HK-II complex by these peptides effectively triggers mitochondria-mediated apoptosis.
- These peptide constructs represent a promising new avenue for targeted melanoma therapy.
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