A prostate-specific antigen-dependent fusion polypeptide inhibits growth of prostate cancer cells in vitro and in vivo.
Polypeptide APP8 is a prostate-specific antigen (PSA)-activated prodrug that was designed to synergize the effects of the Bcl-2 homology domain 3 (BH3) peptide, K237 and the DG2 peptide. The aim of this study is to evaluate its biodistribution and anticancer effect in vitro and in vivo. In this study, APP8 and each component peptide were synthesized. The biodistribution was identified using con-focal microscopyin both PSA(+) cell line and PSA(-) cell line in vitro. Then cell cycle, MTT and in-cell western blot were accessed to analyze the effect mechanisms. Finally, xenografts were used to confirm the anticancer effect in vivo. Here, it was shown that APP8 was hydrolyzed and BH3 was released into the nucleus, while K237 and DG2 were located predominantly in the cytoplasm, only in LNCaP cells (PSA(+)), but not PC3 cells (PSA(-)). K237 and DG2 could induce cell apoptosis through decreasing the phosphorylation of ERK-2 and Flk-1. APP8 also caused the death of LNCaP cells, and was predominantly dependent on BH3 in vitro. In addition, It was noted that as the tumor grew in vivo, APP8 could inhibit the tumor volume to 77.3%, mainly depending on K237 and DG2 via inhibition of the growth of vascular endothelial cells. Our results suggested that APP8 could promote prostate cancer cell death and stop prostate cancer growth via synergizing apoptosis induction of tumor cell and inhibition of the growth of vascular endothelial cells. It provides a novel candidate prodrug for specific therapy of prostate cancer.
Department of Clinical Laboratory Medicine, Xijing Hospital, Fourth Military Medical UniversityXi'an 710032, China; Department of Immunology, Fourth Military Medical UniversityXi'an 710032, China.
Xiang
X
Zhang
Department of Clinical Laboratory Medicine, Xijing Hospital, Fourth Military Medical University Xi'an 710032, China.
Yueyun
Y
Ma
Department of Clinical Laboratory Medicine, Xijing Hospital, Fourth Military Medical University Xi'an 710032, China.
Hua
H
Wei
Department of Clinical Laboratory Medicine, Xijing Hospital, Fourth Military Medical University Xi'an 710032, China.
Bin
B
Li
Department of Clinical Laboratory Medicine, Xijing Hospital, Fourth Military Medical University Xi'an 710032, China.
Fengjing
F
Xiao
Department of Clinical Laboratory Medicine, Xijing Hospital, Fourth Military Medical University Xi'an 710032, China.
Jing
J
Yang
Department of Clinical Laboratory Medicine, Xijing Hospital, Fourth Military Medical University Xi'an 710032, China.
Qiaohong
Q
Yue
Department of Immunology, Fourth Military Medical University Xi'an 710032, China.
Angang
A
Yang
Department of Clinical Laboratory Medicine, Xijing Hospital, Fourth Military Medical University Xi'an 710032, China.
Xiaoke
X
Hao
APP8; Bcl-2 homology domain 3; ERK-2; Flk-1; Prostate-specificantigen