title: A recombinantly tailored β-defensin that displays intensive macropinocytosis-mediated uptake exerting potent efficacy against K-Ras mutant pancreatic cancer.
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.
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Perking Union Medical College, Beijing, P.R. China.
authors: Yue
authors: Y
authors: Du
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Perking Union Medical College, Beijing, P.R. China.
authors: Bo-Yang
authors: BY
authors: Shang
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Perking Union Medical College, Beijing, P.R. China.
authors: Wei-Jin
authors: WJ
authors: Sheng
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Perking Union Medical College, Beijing, P.R. China.
authors: Sheng-Hua
authors: SH
authors: Zhang
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Perking Union Medical College, Beijing, P.R. China.
authors: Yi
authors: Y
authors: Li
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Perking Union Medical College, Beijing, P.R. China.
authors: Qing-Fang
authors: QF
authors: Miao
authors: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Perking Union Medical College, Beijing, P.R. China.
authors: Yong-Su
authors: YS
authors: Zhen
mesh_terms: D000072283:A549 Cells; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D011905:Genes, ras; D005822:Genetic Vectors; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D010873:Pinocytosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D000075462:Serum Albumin, Human / Q000378:metabolism*; D023083:beta-Defensins / Q000378:metabolism*
chemical_list: C106641:DEFB4A protein, human; C117307:KRAS protein, human; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D023083:beta-Defensins; D016283:Proto-Oncogene Proteins p21(ras); D000075462:Serum Albumin, Human
keywords: K-Ras mutant; macropinocytosis; pancreatic cancer; targeting therapy; β-defensin