Oncotarget

Research Papers:

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

Yue Du, Bo-yang Shang, Wei-jin Sheng, Sheng-hua Zhang, Yi Li, Qing-fang Miao and Yong-su Zhen _

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Oncotarget. 2016; 7:58418-58434. https://doi.org/10.18632/oncotarget.11170

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Abstract

Yue Du1, Bo-yang Shang1, Wei-jin Sheng1, Sheng-hua Zhang1, Yi Li1, Qing-fang Miao1, Yong-su Zhen1

1Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Perking Union Medical College, Beijing, P.R. China

Correspondence to:

Yong-su Zhen, email: [email protected]

Keywords: β-defensin, macropinocytosis, K-Ras mutant, pancreatic cancer, targeting therapy

Received: March 06, 2016    Accepted: July 27, 2016    Published: August 10, 2016

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.


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