Hexokinase II-Derived Cell-Penetrating Peptide Mediates Delivery of MicroRNA Mimic for Cancer-Selective Cytotoxicity

L. Palanikumar, Sumaya Al-Hosani, Mona Kalmouni, Hadi Omar Saleh, Mazin Magzoub

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2259-2273
Number of pages15
JournalBiochemistry
Volume59
Issue number24
DOIs
StatePublished - Jun 23 2020

ASJC Scopus subject areas

  • Biochemistry

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