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

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Hexokinase II-Derived Cell-Penetrating Peptide Mediates Delivery of MicroRNA Mimic for Cancer-Selective Cytotoxicity.
Biochemistry ( IF 2.9 ) Pub Date : 2020-06-03 , DOI: 10.1021/acs.biochem.0c00141
L Palanikumar ₁ , Sumaya Al-Hosani ₁ , Mona Kalmouni ₁ , Hadi Omar Saleh ₁ , Mazin Magzoub ₁

Affiliation

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.

中文翻译：

己糖激酶II衍生的细胞穿透肽介导MicroRNA模拟物对癌症选择性细胞毒性的传递。

癌细胞通常以线粒体结合的己糖激酶II（HKII）水平升高为特征，这有助于其生存，增殖和转移。在这里，我们通过将短促穿透序列（PAS）与HKII（pHK）的线粒体膜结合N端15个氨基酸共价偶联，设计了一种癌症选择性细胞穿透肽（CPP）。PAS-pHK介导miR-126（一种在许多恶性肿瘤中下调的抑癌miRNA）的合成模拟物的有效细胞摄取和胞质传递。乳腺癌MCF-7细胞摄取后，CPP-miRNA偶联物分布在整个细胞质中，并显示出与线粒体的强烈共定位作用，其中PAS-pHK诱导线粒体膜电位去极化，抑制代谢活性，消耗细胞内ATP水平，c，最后是凋亡。同时，miR-126货物协同增强了PAS-pHK的抗癌作用。重要的是，PAS-pHK–miR-126偶联物对非癌性MCF-10A和HEK-93细胞无毒。我们的结果证明了PAS-pHK介导的miRNA模拟物传递作为新的癌症选择性治疗策略的潜力。

更新日期：2020-06-23

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