Related Experiment Video
Updated: May 20, 2025
Biotinylated Cell-penetrating Peptides to Study Intracellular Protein-protein Interactions
Published on: December 20, 2017
Targeting Cancer With Bifunctional Peptides: Mechanism of Cell Entry and Inciting Cell Death
Maria F Setiawan1, Oliver Rudan1, Ingo G H Schmidt-Wolf1
1Department for Integrated Oncology, University Hospital of Bonn, Bonn, Germany.
Abstract:
Antimicrobial peptides have gained much attention in clinical research due to their extensive possibilities of application beyond antimicrobial use. The modification of antimicrobial peptides enables the peptides to target particular cancer cells, improving the specificity and efficiency of the treatment. In this study, TP2-D-Tox, a derivative of TP-D-Tox, demonstrated a superior anti-tumor activity towards renal carcinoma, Caki-2, and breast carcinoma, SK-BR-3. TP-Tox was previously reported to inhibit tumor growth in a mouse model, increasing the overall survival. TP- and TP2-D-Tox were shown to penetrate the cells via clathrin-mediated endocytosis, triggered by binding to the subunits of non-muscle myosin IIa and S100A9. HSPB1 was observed to have a protective effect towards TP2-D-Tox against the immediate proteolytic inactivation. The intracellular presence of the peptides evoked mitochondrial permeability transition, generation of reactive oxygen species, and formation of MLKL oligomers in the plasma membrane. Our investigation revealed that TP- and TP2-D-Tox induced a similar but distinctly regulated cell death in Caki-2 and SK-BR-3 cells. Both peptides established toxicity without activating any caspases, suggesting the possibility of TP- and TP2-D-Tox as a promising approach to bypass the caspase-dependent apoptosis-resistance issue impairing therapeutic responses of many cancer treatments.
Insights
Modified antimicrobial peptides, TP- and TP2-D-Tox, show potent anti-tumor effects against renal and breast cancers. These peptides induce cell death independently of caspases, offering a novel therapeutic strategy for resistant cancers.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Antimicrobial peptides (AMPs) are explored for non-antimicrobial applications, including cancer therapy.
- Modifying AMPs enhances targeting specificity and efficacy against cancer cells.
- Previous work showed TP-Tox inhibits tumor growth and improves survival in mouse models.
Purpose of the Study:
- To evaluate the anti-tumor activity of TP2-D-Tox, a derivative of TP-D-Tox, against renal (Caki-2) and breast (SK-BR-3) carcinoma cells.
- To elucidate the mechanism of action, including cellular uptake and cell death pathways induced by TP- and TP2-D-Tox.
- To assess the potential of these peptides as a therapeutic strategy for overcoming caspase-dependent apoptosis resistance in cancer.
Main Methods:
- Cellular uptake studies using clathrin-mediated endocytosis.
- Investigation of intracellular signaling pathways, including mitochondrial effects and reactive oxygen species generation.
- Analysis of cell death mechanisms, focusing on MLKL oligomerization and caspase activation.
Main Results:
- TP2-D-Tox exhibited superior anti-tumor activity against Caki-2 and SK-BR-3 cells compared to TP-D-Tox.
- Peptide uptake occurred via clathrin-mediated endocytosis, facilitated by binding to non-muscle myosin IIa and S100A9.
- HSPB1 protected TP2-D-Tox from proteolytic inactivation.
- Intracellular peptide presence triggered mitochondrial dysfunction, ROS generation, and MLKL oligomerization.
- TP- and TP2-D-Tox induced caspase-independent cell death in cancer cells.
Conclusions:
- TP- and TP2-D-Tox demonstrate significant anti-tumor efficacy against renal and breast carcinomas.
- These peptides induce a unique, regulated form of cell death that bypasses caspase activation.
- The findings suggest TP- and TP2-D-Tox are promising candidates for cancer therapy, particularly for overcoming apoptosis resistance.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
01:31The Intrinsic Apoptotic Pathway
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
01:17The Extrinsic Apoptotic Pathway
02:38Mitogens and the Cell Cycle
01:30Overview of Cell Death
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the...