Proapoptotic Peptide-Mediated Cancer Therapy Targeted to Cell Surface p32
Proapoptotic Peptide-Mediated Cancer Therapy Targeted to Cell Surface p32
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DOI：
10.1038/mt.2013.191
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发表时间：
2013-12-01
影响因子：
12.4
通讯作者：
Ruoslahti, Erkki
中科院分区：
文献类型：
--
作者：
Agemy, Lilach;Kotamraju, Venkata R.;Ruoslahti, Erkki
抗血管生成疗法是一种有前途的癌症新治疗方式，但它通常只能产生短暂的肿瘤消退。我们之前设计了一种肿瘤靶向纳米系统，其中五肽 CGKRK 将促凋亡肽递送到肿瘤血管内皮细胞和肿瘤细胞的线粒体中。该治疗对于其他抗血管生成治疗完全无效的胶质母细胞瘤小鼠模型非常有效。在这里，我们鉴定出 p32/gC1qR/HABP，一种线粒体蛋白，也在活化（血管生成）内皮细胞和肿瘤细胞的细胞表面表达，作为 CGKRK 肽的受体。结果证明 p32 能够使与 p32 结合的有效负载内化到细胞质中。我们还表明，nardilysin（一种能够裂解 CGKRK 的蛋白酶）在 p32 结合有效负载的内化中发挥作用。由于 p32 在乳腺癌中过度表达并在表面展示，我们研究了纳米系统在这种癌症中的功效。我们在乳腺癌原位模型中展示了非常显着的治疗结果。细胞表面 p32 对肿瘤相关细胞的特异性、其将有效负载携带至线粒体的能力以及该系统在重要类型癌症中的功效，使该纳米系统成为进一步开发的有希望的候选者。
Antiangiogenic therapy is a promising new treatment modality for cancer, but it generally produces only transient tumor regression. We have previously devised a tumor-targeted nanosystem, in which a pentapeptide, CGKRK, delivers a proapoptotic peptide into the mitochondria of tumor blood vessel endothelial cells and tumor cells. The treatment was highly effective in glioblastoma mouse models completely refractory to other antiangiogenic treatments. Here, we identify p32/gC1qR/HABP, a mitochondrial protein that is also expressed at the cell surface of activated (angiogenic) endothelial cells and tumor cells, as a receptor for the CGKRK peptide. The results demonstrate the ability of p32 to cause internalization of a payload bound to p32 into the cytoplasm. We also show that nardilysin, a protease capable of cleaving CGKRK, plays a role in the internalization of a p32-bound payload. As p32 is overexpressed and surface displayed in breast cancers, we studied the efficacy of the nanosystem in this cancer. We show highly significant treatment results in an orthotopic model of breast cancer. The specificity of cell surface p32 for tumor-associated cells, its ability to carry payloads to mitochondria, and the efficacy of the system in important types of cancer make the nanosystem a promising candidate for further development.