Induction of autophagic cell death of glioma-initiating cells by cell-penetrating D-isomer peptides consisting of Pas and the p53 C-terminus.
Induction of autophagic cell death of glioma-initiating cells by cell-penetrating D-isomer peptides consisting of Pas and the p53 C-terminus.
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DOI：
10.1016/j.biomaterials.2012.09.003
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发表时间：
2012-12
期刊：
影响因子：
14
通讯作者：
Yutaka Ueda;Fan-Yan Wei;T. Hide;H. Michiue;Kentaro Takayama;T. Kaitsuka;Hideo Nakamura;K. Makino;J. Kuratsu;S. Futaki;K. Tomizawa
中科院分区：
文献类型：
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作者：
Yutaka Ueda;Fan-Yan Wei;T. Hide;H. Michiue;Kentaro Takayama;T. Kaitsuka;Hideo Nakamura;K. Makino;J. Kuratsu;S. Futaki;K. Tomizawa
多形性胶质母细胞瘤是最具侵袭性和致命性的脑肿瘤。GBM对化疗和放疗具有耐药性。近年来的研究表明，胶质瘤起始细胞（glioma- initiation cells, GICs）具有肿瘤干细胞的特性，是肿瘤抗化疗、抗放疗和再生的重要机制。目前还没有针对gic的有效治疗方法。本研究表明，由细胞穿透肽（FHV）、穿透加速序列（Pas）和p53的c端（p53C ‘）组成的d-异构体肽（dPasFHV-p53C ’）可诱导gic细胞死亡。dPasFHV-p53C '被有效地转导到人类gic中。多肽剂量依赖性地抑制细胞生长，在3 μM时完全阻断GICs的生长，但不阻断胚胎干细胞的生长。dPasFHV-p53C '处理的GICs细胞出现自噬性死亡，但未出现细胞凋亡。不含p53C ‘的dPasFHV表现出与dPasFHV-p53C ’相同的效果，表明Pas在GICs细胞死亡中起关键作用。最后，dPasFHV-p53C '减少了GICs移植小鼠的肿瘤质量。利用dPasFHV-p53C′进行多肽转导治疗有望成为治疗GBM的新方法。
Glioblastoma multiforme (GBM) is the most aggressive and fatal brain tumor. GBM is resistant to chemotherapy and radiation. Recent studies have shown that glioma-initiating cells (GICs), which have characteristics of cancer stem cells, are responsible for the resistance to chemotherapy and radiation and regrowth. No effective therapy for GICs has been developed. Here we showed that d-isomer peptides (dPasFHV-p53C′) consisting of a cell-penetrating peptide (FHV), penetration accelerating sequence (Pas) and C-terminus of p53 (p53C′) induced the cell death of GICs. dPasFHV-p53C′ was effectively transduced into human GICs. The peptides dose-dependently inhibited cell growth and at 3 μM completely blocked the growth of GICs but not embryonic stem cells. Autophagic cell death was observed in the GICs treated with dPasFHV-p53C′ but apoptosis was not. dPasFHV without p53C′ showed the same effect as dPasFHV-p53C′, suggesting Pas to play a critical role in the cell death of GICs. Finally, dPasFHV-p53C′ reduced tumor mass in mice transplanted with GICs. Peptide transduction therapy using dPasFHV-p53C′ could be a new method for the treatment of GBM.