Hexokinase II-Derived Cell-Penetrating Peptide Mediates Delivery of MicroRNA Mimic for Cancer-Selective CytotoxicityClick to copy article linkArticle link copied!
- L. PalanikumarL. PalanikumarBiology Program, Division of Science, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island Campus, Abu Dhabi, United Arab EmiratesMore by L. Palanikumar
- Sumaya Al-HosaniSumaya Al-HosaniBiology Program, Division of Science, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island Campus, Abu Dhabi, United Arab EmiratesMore by Sumaya Al-Hosani
- Mona KalmouniMona KalmouniBiology Program, Division of Science, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island Campus, Abu Dhabi, United Arab EmiratesMore by Mona Kalmouni
- Hadi Omar SalehHadi Omar SalehBiology Program, Division of Science, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island Campus, Abu Dhabi, United Arab EmiratesMore by Hadi Omar Saleh
- Mazin Magzoub*Mazin Magzoub*Biology Program, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island Campus, Abu Dhabi, United Arab Emirates. Telephone: +971-2-628-4760. Fax: +971-2-659-0791. Email: [email protected]Biology Program, Division of Science, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island Campus, Abu Dhabi, United Arab EmiratesMore by Mazin Magzoub
Abstract
Cancer cells are often characterized by elevated levels of mitochondrion-bound hexokinase II (HKII), which facilitates their survival, proliferation, and metastasis. Here, we have designed a cancer-selective cell-penetrating peptide (CPP) by covalently coupling a short penetration-accelerating sequence (PAS) to the mitochondrial membrane-binding N-terminal 15 amino acids of HKII (pHK). PAS-pHK mediates efficient cellular uptake and cytosolic delivery of a synthetic mimic of miR-126, a tumor suppressor miRNA downregulated in many malignancies. Following uptake by breast cancer MCF-7 cells, the CPP–miRNA conjugate is distributed throughout the cytosol and shows strong colocalization with mitochondria, where PAS-pHK induces depolarization of mitochondrial membrane potential, inhibition of metabolic activities, depletion of intracellular ATP levels, release of cytochrome c, and, finally, apoptosis. Concomitantly, the miR-126 cargo synergistically enhances the anticancer effects of PAS-pHK. Importantly, the PAS-pHK–miR-126 conjugate is not toxic to noncancerous MCF-10A and HEK-93 cells. Our results demonstrate the potential of PAS-pHK-mediated delivery of miRNA mimics as a novel cancer-selective therapeutic strategy.
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