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一种经重组定制的β-防御素，其表现出强烈的巨胞饮作用介导的摄取，对K-Ras突变型胰腺癌具有强大疗效。

A recombinantly tailored β-defensin that displays intensive macropinocytosis-mediated uptake exerting potent efficacy against K-Ras mutant pancreatic cancer.

作者信息

Du Yue, Shang Bo-Yang, Sheng Wei-Jin, Zhang Sheng-Hua, Li Yi, Miao Qing-Fang, Zhen Yong-Su

机构信息

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Perking Union Medical College, Beijing, P.R. China.

出版信息

Oncotarget. 2016 Sep 6;7(36):58418-58434. doi: 10.18632/oncotarget.11170.

DOI:10.18632/oncotarget.11170
PMID:27517152
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5295440/
Abstract

K-Ras mutant pancreatic cancer cells display intensive macropinocytosis, indicating that this process may be exploited in the design of anticancer targeted therapies. In this study, we constructed a macropinocytosis-oriented recombinantly tailored defensin (DF-HSA) which consists of human β-defensin-2 (DF) and human serum albumin (HSA). The macropinocytosis intensity and cytotoxicity of DF-HSA were investigated in K-Ras mutant MIA PaCa-2 cells and wild-type BxPC-3 cells. As found, the DF-HSA uptake in MIA PaCa-2 cells was much higher than that in wild-type BxPC-3 cells. Correspondingly, the cytotoxicity of DF-HSA to MIA PaCa-2 cells was more potent than that to BxPC-3 cells. In addition, the cytotoxicity of DF-HSA was much stronger than that of β-defensin HBD2. DF-HSA suppressed cancer cell proliferation and induced mitochondrial pathway apoptosis. Notably, DF-HSA significantly inhibited the growth of human pancreatic carcinoma MIA PaCa-2 xenograft in athymic mice at well tolerated dose. By in vivo imaging, DF-HSA displayed a prominent accumulation in the tumor. The study indicates that the recombinantly tailored β-defensin can intensively enter into the K-Ras mutant pancreatic cancer cells through macropinocytosis-mediated process and exert potent therapeutic efficacy against the pancreatic carcinoma xenograft. The novel format of β-defensin may play an active role in macropinocytosis-mediated targeting therapy.

摘要

K-Ras 突变型胰腺癌细胞表现出强烈的巨胞饮作用，这表明该过程可用于设计抗癌靶向治疗。在本研究中，我们构建了一种以巨胞饮作用为导向的重组定制防御素（DF-HSA），它由人β-防御素-2（DF）和人血清白蛋白（HSA）组成。在 K-Ras 突变型 MIA PaCa-2 细胞和野生型 BxPC-3 细胞中研究了 DF-HSA 的巨胞饮作用强度和细胞毒性。结果发现，MIA PaCa-2 细胞对 DF-HSA 的摄取远高于野生型 BxPC-3 细胞。相应地，DF-HSA 对 MIA PaCa-2 细胞的细胞毒性比对 BxPC-3 细胞更强。此外，DF-HSA 的细胞毒性比β-防御素 HBD2 强得多。DF-HSA 抑制癌细胞增殖并诱导线粒体途径凋亡。值得注意的是，DF-HSA 在耐受性良好的剂量下显著抑制了无胸腺小鼠中人胰腺癌 MIA PaCa-2 异种移植瘤的生长。通过体内成像，DF-HSA 在肿瘤中显示出显著的积聚。该研究表明，重组定制的β-防御素可通过巨胞饮作用介导的过程大量进入 K-Ras 突变型胰腺癌细胞，并对胰腺癌异种移植瘤发挥强大的治疗效果。β-防御素的这种新形式可能在巨胞饮作用介导的靶向治疗中发挥积极作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2239/5295440/f5a79cc9038c/oncotarget-07-58418-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2239/5295440/813315f67731/oncotarget-07-58418-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2239/5295440/74ea33b3a505/oncotarget-07-58418-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2239/5295440/ed6f15df563e/oncotarget-07-58418-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2239/5295440/5b2cf9b11ad1/oncotarget-07-58418-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2239/5295440/24bf6b3e5e0e/oncotarget-07-58418-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2239/5295440/3ae965f381a1/oncotarget-07-58418-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2239/5295440/f5a79cc9038c/oncotarget-07-58418-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2239/5295440/813315f67731/oncotarget-07-58418-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2239/5295440/74ea33b3a505/oncotarget-07-58418-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2239/5295440/ed6f15df563e/oncotarget-07-58418-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2239/5295440/5b2cf9b11ad1/oncotarget-07-58418-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2239/5295440/24bf6b3e5e0e/oncotarget-07-58418-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2239/5295440/3ae965f381a1/oncotarget-07-58418-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2239/5295440/f5a79cc9038c/oncotarget-07-58418-g007.jpg

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