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Published on: September 28, 2019
Mitochondria-specific peptide amphiphiles induce mitochondrial dysfunction and peripheral T-cell lymphomas (PTCL)
Qi Sun1, Ailing Gui1, Aihua Zou2
1Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Background:
Peripheral T-cell lymphomas (PTCL) are aggressive lymphomas with poor prognosis, and therefore, there is a pressing need to explore new targets or compounds. Mitochondria may serve as a potential therapeutic target for PTCL. A designed positively-charged segment (pKV) is anchored to the specific 15 amino acid sequence (MIASHLLAYFFTELN) to yield a cell-penetrating peptide (pHK-pKV) and a lipid chain (Pal) is conjugated to the N-terminus of pHK-pKV (Pal-pHK-pKV) are bioactive amphiphilic peptide assemblies targeting the interaction between mitochondrial voltage dependent anion channel 1 (VDAC1) and hexokinase II (HKII).
Methods:
PTCL cell line H9 was treated with Pal-pHK-pKV and pHK-pKV, respectively. Cell proliferation in each group was measured by detecting cell viability and the corresponding marker Ki-67. Apoptosis was detected by immunofluorescence, flow cytometry and western blot. We also measured mitochondrial membrane potential, adenosine triphosphate (ATP) production, the cytochrome c distribution and the expression levels of B cell lymphoma 2 (BCL-2) and BCL-2 associated X protein (BAX). Western blot was used to detect the activation of the extracellular regulated protein kinases (ERK) signaling pathway.
Results:
Pal-pHK-pKV and pHK-pKV with 20 µM blocked the interaction between VDAC1 and HKII, and detached HKII from mitochondria, which depolarized the mitochondrial membrane potential, induced mitochondria dysfunction, and decreased ATP production. The decreased ATP subsequently inhibited the activation of the ERK/BCL-2 pathway and increased the BAX/BCL-2 ratio. Cytochrome c was then released from the mitochondria and induced capase-3 activation and subsequently apoptosis. Additionally, decreased ATP induced the expression of FAS and then apoptosis.
Conclusions:
Mitochondria specific peptide amphiphiles induce mitochondrial dysfunction and provide a new approach for the treatment of PTCL.
Insights
New peptide amphiphiles target mitochondria in peripheral T-cell lymphomas (PTCL). These compounds disrupt mitochondrial function, leading to apoptosis and offering a novel therapeutic strategy for aggressive PTCL.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Peripheral T-cell lymphomas (PTCL) are aggressive cancers with limited treatment options.
- Mitochondria represent a promising therapeutic target for PTCL due to their role in cell survival.
- Novel peptide amphiphiles were designed to target mitochondrial VDAC1-HKII interactions.
Purpose of the Study:
- To investigate the efficacy of peptide amphiphiles (Pal-pHK-pKV and pHK-pKV) in treating PTCL.
- To elucidate the mechanism of action of these peptides on mitochondrial function and apoptosis.
- To evaluate the potential of targeting mitochondrial VDAC1-HKII interaction for PTCL therapy.
Main Methods:
- Treatment of PTCL cell line H9 with peptide amphiphiles.
- Assessment of cell proliferation, apoptosis markers (Ki-67, cytochrome c, caspase-3), and mitochondrial function (membrane potential, ATP production).
- Analysis of signaling pathways including ERK/BCL-2 and expression of BAX and FAS.
Main Results:
- Peptide amphiphiles effectively blocked VDAC1-HKII interaction, detaching HKII from mitochondria.
- Mitochondrial dysfunction, decreased ATP production, and depolarization of mitochondrial membrane potential were observed.
- Induction of apoptosis through intrinsic and extrinsic pathways (cytochrome c release, FAS expression) and inhibition of ERK/BCL-2 signaling.
Conclusions:
- Mitochondria-specific peptide amphiphiles induce mitochondrial dysfunction and apoptosis in PTCL cells.
- These compounds represent a novel therapeutic approach for PTCL by targeting VDAC1-HKII interaction.
- Further research into peptide amphiphiles holds promise for developing new PTCL treatments.
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