Hexokinase II-derived cell-penetrating peptide targets mitochondria and triggers apoptosis in cancer cells

Abiy D. Woldetsadik, Maria C. Vogel, Wael Rabeh, Mazin Magzoub

    Research output: Contribution to journalArticle

    Abstract

    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 pHKPAS 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.

    Original languageEnglish (US)
    Pages (from-to)2168-21874
    Number of pages19707
    JournalFASEB Journal
    Volume31
    Issue number5
    DOIs
    StatePublished - May 1 2017

    Fingerprint

    Cell-Penetrating Peptides
    Mitochondria
    Hexokinase
    Cells
    Apoptosis
    Cytotoxicity
    Neoplasms
    Membranes
    Peptides
    Mitochondrial Membrane Potential
    HEK293 Cells
    Mitochondrial Membranes
    Glycolysis
    Cytochromes c
    HeLa Cells
    Respiration
    Adenosine Triphosphate
    Association reactions
    Growth

    Keywords

    • ATP
    • Cytochrome c
    • Cytotoxicity
    • Glycolysis
    • Oxidative phosphorylation

    ASJC Scopus subject areas

    • Biotechnology
    • Biochemistry
    • Molecular Biology
    • Genetics

    Cite this

    Hexokinase II-derived cell-penetrating peptide targets mitochondria and triggers apoptosis in cancer cells. / Woldetsadik, Abiy D.; Vogel, Maria C.; Rabeh, Wael; Magzoub, Mazin.

    In: FASEB Journal, Vol. 31, No. 5, 01.05.2017, p. 2168-21874.

    Research output: Contribution to journalArticle

    Woldetsadik, Abiy D. ; Vogel, Maria C. ; Rabeh, Wael ; Magzoub, Mazin. / Hexokinase II-derived cell-penetrating peptide targets mitochondria and triggers apoptosis in cancer cells. In: FASEB Journal. 2017 ; Vol. 31, No. 5. pp. 2168-21874.
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