Hexokinase II-derived cell-penetrating peptide targets mitochondria and triggers apoptosis in cancer cells.
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 cytochromecOf 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.
Division of Science, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates.
Abiy D
AD
Woldetsadik
Division of Science, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates.
Maria C
MC
Vogel
Division of Science, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates.
Wael M
WM
Rabeh
Division of Science, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates mazin.magzoub@nyu.edu.
Mazin
M
Magzoub
D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology; D057809:HEK293 Cells; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*
D057846:Cell-Penetrating Peptides; D045304:Cytochromes c; D006593:Hexokinase
ATP; cytochrome c; cytotoxicity; glycolysis; oxidative phosphorylation