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.
Highlights
Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and its contents are internalized into cells through large, heterogeneous vesicles known as macropinosomes [1]
It is reported that K-Ras-transformed human pancreatic adenocarcinoma-derived MIA PaCa2 cells display appreciably higher levels of macropinocytosis compared to wild-type K-Ras expressing BxPC-3 cells
The macropinocytosis inhibitor EIPA can significantly reduce the uptake of a large amount of albumin and inhibit tumor xenograft growth of pancreatic carcinoma MIA PaCa-2 cells that display intensive macropinocytosis
Summary
Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and its contents are internalized into cells through large, heterogeneous vesicles known as macropinosomes [1]. Owing to the large size of macropinosomes, the process provides cells with a fast and effective way to internalize extracellular nutrients and solute molecules [2]. Most cells do not exhibit macropinocytic activity under normal culture conditions, while macropinocytosis widely exists in tumor cells; it is an important nutrient delivery pathway that cancer cells use to drive their proliferation and growth [3, 4]. K-Ras-transformed cells intensely depend on enhanced macropinocytosis to transport extracellular proteins into the cells for maintaining their proliferation and growth. Modulation of the macropinocytosis process might serve as a promising strategy for the development of novel cancer www.impactjournals.com/oncotarget targeted therapeutics. It is feasible to employ albumin as a carrier for macropinocytosismediated targeting therapy
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