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Selective induction of apoptosis through the FADD/caspase-8 pathway by a p53 c-terminal peptide in human pre-malignant and malignant cells
Journal article   Open access   Peer reviewed

Selective induction of apoptosis through the FADD/caspase-8 pathway by a p53 c-terminal peptide in human pre-malignant and malignant cells

Yin Li, Yuehua Mao, Ramon V Rosal, Richard D Dinnen, Ann C Williams, Paul W Brandt-Rauf and Robert L Fine
International journal of cancer, v 115(1)
20 May 2005
DOI: https://doi.org/10.1002/ijc.20838
PMID: 15645452
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ijc.20838View
Published, Version of Record (VoR) Open
url
https://doi.org/10.1002/ijc.20838View
Published, Version of Record (VoR) Open

Abstract

Apoptosis Apoptosis Regulatory Proteins Arabidopsis Proteins - metabolism Blotting, Western Caspase 8 Caspases - metabolism Cell Line, Tumor Dose-Response Relationship, Drug Enzyme Activation Enzyme Inhibitors - pharmacology fas Receptor - metabolism Fatty Acid Desaturases - metabolism Flow Cytometry - methods Genes, Dominant Humans L-Lactate Dehydrogenase - metabolism Membrane Glycoproteins - metabolism Microscopy, Fluorescence Mutation Necrosis Peptides - chemistry Phenotype Plasmids - metabolism Precancerous Conditions Protein Binding Protein Structure, Tertiary Proto-Oncogene Proteins c-bcl-2 - chemistry Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Surface Plasmon Resonance Temperature Time Factors TNF-Related Apoptosis-Inducing Ligand Transfection Tumor Necrosis Factor-alpha - metabolism Tumor Suppressor Protein p53 - chemistry Tumor Suppressor Protein p53 - metabolism
A p53 C-terminal peptide (aa 361-382, p53p), fused at its C-terminus to the minimal carrier peptide of antennapedia (17 aa, Ant; p53p-Ant), induced rapid apoptosis in human cancer cells, via activation of the Fas pathway. We examined p53p-Ant mechanism of action, toxicity in various human normal, non-malignant, pre-malignant and malignant cancer cells and investigated its biophysical characteristics. p53p-Ant selectively induced cell death in only pre-malignant or malignant cells in a p53-dependent manner and was not toxic to normal and non-malignant cells. p53p-Ant was more toxic to the mutant p53 than wild-type p53 phenotype in H1299 lung cancer cells stably expressing human temperature-sensitive p53 mutant 143Ala. Surface plasmon resonance (BIACORE) analysis demonstrated that this peptide had higher binding affinity to mutant p53 as compared to wild-type p53. p53p-Ant induced-cell death had the classical morphological characteristics of apoptosis and had no features of necrosis. The mechanism of cell death by p53p-Ant was through the FADD/caspase-8-dependent pathway without the involvement of the TRAIL pathway, Bcl-2 family and cell cycle changes. Blocking Fas with antibody did not alter the peptide's effect, suggesting that Fas itself did not interact with the peptide. Transfection with a dominant-negative FADD with a deleted N-terminus inhibited p53p-Ant-induced apoptosis. Its mechanism of action is related to the FADD-induced pathway without restoration of other p53 functions. p53p-Ant is a novel anticancer agent with unique selectivity for human cancer cells and could be useful as a prototype for the development of new anti-cancer agents.

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23 citations in Web of Science
30 citations in Scopus

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Domestic collaboration
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Web of Science research areas
Oncology
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