Peptide-based tumor inhibitor encoding mitochondrial p14(ARF) is highly efficacious to diverse tumors.
Peptide-based tumor inhibitor encoding mitochondrial p14(ARF) is highly efficacious to diverse tumors.
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DOI：
10.1111/cas.12991
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发表时间：
2016-09
期刊：
影响因子：
5.7
通讯作者：
Kondo E
中科院分区：
文献类型：
--
作者：
Saito K;Iioka H;Kojima C;Ogawa M;Kondo E
p14 ARF是一种主要的肿瘤抑制因子，通常被鉴定为mdm 2结合分子，恢复细胞核中的p53功能，并作为核仁内的核磷蛋白结合伴侣稳定核糖体RNA。然而，最近报道的线粒体定位指出了新的特性作为一种肿瘤抑制剂。与此同时，功能肽在纳米医学中因其作为非侵入性生物制剂的体内效用而受到广泛关注。我们先前报道了p14 ARF特异性肽，其恢复了吉非替尼耐药肺癌细胞对吉非替尼的敏感性。基于这种原型肽的信息，我们在这里产生了更强大的抗肿瘤肽“r9-CatB-p14 MIS”，其包含线粒体靶向p14 ARF蛋白的最小抑制序列与组织蛋白酶B的蛋白水解切割位点的组合，组织蛋白酶B在各种肿瘤细胞中被激活，与用于细胞穿透的九聚精氨酸结构域融合，并证实了其根据内源性p14 ARF的定位调节线粒体功能的新作用。p14 MIS肽通过调节线粒体膜电位，在体外和体内显示出不仅针对肺癌细胞而且针对不同谱系的肿瘤细胞的有效肿瘤抑制剂，对非肿瘤细胞和组织具有最小的细胞毒性。因此，这种靶向p14肽药物为基于非侵入性肽的抗肿瘤治疗提供了新的基础。
p14 ARF is one of the major tumor suppressors conventionally identified both as the mdm2‐binding molecule restoring p53 function in the nucleus, and as a nucleophosmin‐binding partner inside the nucleolous to stabilize ribosomal RNA. However, its recently reported mitochondrial localization has pointed to novel properties as a tumor suppressor. At the same time, functional peptides are gaining much attention in nanomedicine for their in vivo utility as non‐invasive biologics. We previously reported the p14ARF‐specific peptide that restored the sensitivity to gefitinib on the gefitinib‐resistant lung cancer cells. Based on the information of this prototype peptide, here we generated the more powerful anti‐tumor peptide “r9‐CatB‐p14 MIS,” which comprises the minimal inhibitory sequence of the mitochondrial targeting p14ARF protein in combination with the proteolytic cleavage site for cathepsin B, which is activated in various tumor cells, fused with the nine‐polyarginine‐domain for cell penetration, and demonstrated its novel action of regulating mitochondrial function in accordance with localization of endogenous p14ARF. The p14 MIS peptide showed a potent tumor inhibiton in vitro and in vivo against not only lung cancer cells but also tumor cells of diverse lineages, via modulating mitochondrial membrane potential, with minimal cytotoxicity to non‐neoplastic cells and tissues. Hence, this mitochondrially targeted p14 peptide agent provides a novel basis for non‐invasive peptide‐based antitumor therapeutics.
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