Hexokinase II-derived cell-penetrating peptide targets mitochondria and triggers apoptosis in cancer cells
Autor: | Mazin Magzoub, Abiy D. Woldetsadik, Maria C. Vogel, Wael M. Rabeh |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
oxidative phosphorylation Apoptosis Oxidative phosphorylation Cell-Penetrating Peptides Mitochondrion Biochemistry HeLa 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor Hexokinase Genetics Humans Glycolysis Molecular Biology biology Chemistry Cytochrome c Research Cytochromes c glycolysis biology.organism_classification Cell biology Mitochondria ATP 030104 developmental biology HEK293 Cells cytochrome c 030220 oncology & carcinogenesis Cancer cell Mitochondrial Membranes biology.protein cytotoxicity Biotechnology |
Zdroj: | The FASEB Journal |
ISSN: | 1530-6860 |
Popis: | Overexpression of mitochondria-bound hexokinase II (HKII) in cancer cells plays an important role in their metabolic reprogramming and protects them against apoptosis, thereby facilitating their growth and proliferation. Here, we show that covalently coupling a peptide corresponding to the mitochondrial membrane–binding N-terminal 15 aa of HKII (pHK) to a short, penetration-accelerating sequence (PAS) enhances the cellular uptake, mitochondrial localization, and cytotoxicity of the peptide in HeLa cells. Further analysis revealed that pHK-PAS depolarized mitochondrial membrane potential, inhibited mitochondrial respiration and glycolysis, and depleted intracellular ATP levels. The effects of pHK-PAS were correlated with dissociation of endogenous full-length HKII from mitochondria and release of cytochrome c. Of significance, pHK-PAS treatment of noncancerous HEK293 cells resulted in substantially lower cytotoxicity. Thus, pHK-PAS effectively disrupted the mitochondria-HKII association in cancer cells, which led to mitochondrial dysfunction and, finally, apoptosis. Our results demonstrate the potential of the pHK-PAS cell-penetrating peptide as a novel therapeutic strategy in cancer.—Woldetsadik, A. D., Vogel, M. C., Rabeh, W. M., Magzoub, M. Hexokinase II–derived cell-penetrating peptide targets mitochondria and triggers apoptosis in cancer cells. |
Databáze: | OpenAIRE |
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