Self-assembly of mitochondria-specific peptide amphiphiles amplifying lung cancer cell death through targeting the VDAC1-hexokinase-II complex
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Synthesis of Monocyte-targeting Peptide Amphiphile Micelles for Imaging of Atherosclerosis
Published on: November 17, 2017
Dan Liu1, Angelina Angelova2, Jianwen Liu3
1Shanghai Key Laboratory of Functional Materials Chemistry, State Key Laboratory of Bioreactor Engineering and Institute of Applied Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, P. R. China. aihuazou@ecust.edu.cn.
Abstract:
Mitochondria-targeting peptides represent an emergent tool for cancer inhibition. Here supramolecular assemblies of novel amphiphilic cell-penetrating peptides for targeting cancer cell mitochondria are reported. The employed strategy aims at amplifying the apoptotic stimuli by weakening the mitochondrial VDAC1 (voltage-dependent anion channel-1)-hexokinase-II (HK-II) interaction. Peptide engineering is performed with the N-terminus of the HK-II protein, which binds to VDAC1. First, a designed positively charged segment (pKV) is anchored to the specific 15 amino acid sequence (MIASHLLAYFFTELN) to yield a cell-penetrating peptide (pHK-pKV). Second, a lipid chain (Pal) is conjugated to the N-terminus of pHK-pKV in order to enhance the intracellular delivery of the HK-II scaffold. The self-assembly properties of these two synthetic peptides are investigated by synchrotron small-angle X-ray scattering (BioSAXS) and cryogenic transmission electron (cryo-TEM) imaging, which evidence the formation of nanoassemblies of ellipsoid-like shapes. Circular dichroism (CD) spectroscopy demonstrates the induction of partial α-helical structures in the amphiphilic peptides. Confocal microscopy reveals the specific mitochondrial location of Pal-pHK-pKV assemblies in human non-small cell lung cancer (NSCLC) A549 cells. The cytotoxicity and apoptotic studies indicate the enhanced bioactivity of Pal-pHK-pKV self-assembled reservoirs, which cause massive A549 cell death with regard to pHK-pKV. Of significance, Pal-pHK-pKV treatment of non-cancerous NCM460 cells resulted in substantially lower cytotoxicity. The results demonstrate the potential of self-assembled lipo-peptide (HK-II-derived) conjugates as a promising strategy in cancer therapy.
Insights
Novel lipo-peptide conjugates target cancer cell mitochondria by disrupting VDAC1-HK-II interactions. These self-assembled peptide nanoassemblies show enhanced cancer cell death with minimal impact on healthy cells, offering a promising cancer therapy strategy.
Area of Science:
- Biochemistry and Molecular Biology
- Nanotechnology
- Cancer Research
Background:
- Mitochondria-targeting peptides are emerging as a strategy for cancer inhibition.
- Disrupting the interaction between voltage-dependent anion channel-1 (VDAC1) and hexokinase-II (HK-II) in mitochondria can amplify apoptotic stimuli.
- Developing novel amphiphilic cell-penetrating peptides for enhanced cancer therapy is crucial.
Purpose of the Study:
- To design and synthesize novel amphiphilic cell-penetrating peptides for targeting cancer cell mitochondria.
- To investigate the self-assembly properties and mitochondrial localization of these peptide constructs.
- To evaluate the efficacy and selectivity of the peptide assemblies in inducing cancer cell death.
Main Methods:
- Peptide engineering involved conjugating a positively charged segment (pKV) and a lipid chain (Pal) to a hexokinase-II (HK-II) derived sequence.
- Synchrotron small-angle X-ray scattering (BioSAXS) and cryogenic transmission electron microscopy (cryo-TEM) were used to characterize nanoassembly formation.
- Circular dichroism (CD) spectroscopy assessed secondary structures, and confocal microscopy confirmed mitochondrial localization in non-small cell lung cancer (NSCLC) A549 cells.
Main Results:
- Synthetic peptides self-assembled into ellipsoid-shaped nanoassemblies.
- The lipo-peptide conjugate (Pal-pHK-pKV) demonstrated specific mitochondrial targeting in A549 cells.
- Pal-pHK-pKV assemblies exhibited significantly enhanced cytotoxicity and apoptosis induction in A549 cells compared to the non-lipidated peptide, with lower toxicity in non-cancerous NCM460 cells.
Conclusions:
- Self-assembled lipo-peptide conjugates derived from HK-II show potential as a targeted cancer therapy.
- Disruption of the VDAC1-HK-II interaction via these peptide assemblies effectively induces cancer cell death.
- The developed peptide strategy offers a promising approach for selective cancer treatment with reduced side effects.
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