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

Abiy D. Woldetsadik, Maria C. Vogel, Wael M. 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 2017

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Keywords

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

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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