TY - JOUR
T1 - Proapoptotic peptide-mediated cancer therapy targeted to cell surface p32
AU - Agemy, Lilach
AU - Kotamraju, Venkata R.
AU - Friedmann-Morvinski, Dinorah
AU - Sharma, Shweta
AU - Sugahara, Kazuki N.
AU - Ruoslahti, Erkki
N1 - Funding Information: We thank Dr Inder Verma (Salk Institute) for comments and Dr Michael J Sailor (University of California, San Diego) and Dr Ji-Ho Park (Korea Advanced Institute of Science and Technology) for advice on the synthesis of iron oxide nanoparticles. This work was supported by grants W81XWH-10-1-0198 and W81XWH-08-1-0727 from the Department of Defense, grants CA152327 and CA012442 from the NIH/NCI, and Cancer Center Support Grants CA030199 and CA014195 from the NCI. VRK, KNS, and ER have ownership interest (including patents) in CendR Therapeutics. ER is the founder, Chairman of the board, consultant/ advisory board member, and major shareholder of CendR Therapeutics and has ownership interest (including patents) in the same. No potential conflicts of interest were disclosed by the other authors.
PY - 2013/12
Y1 - 2013/12
N2 - Antiangiogenic therapy is a promising new treatment modality for cancer, but it generally produces only transient tumor regression. We have previously devised a tumor-targeted nanosystem, in which a pentapeptide, CGKRK, delivers a proapoptotic peptide into the mitochondria of tumor blood vessel endothelial cells and tumor cells. The treatment was highly effective in glioblastoma mouse models completely refractory to other antiangiogenic treatments. Here, we identify p32/gC1qR/HABP, a mitochondrial protein that is also expressed at the cell surface of activated (angiogenic) endothelial cells and tumor cells, as a receptor for the CGKRK peptide. The results demonstrate the ability of p32 to cause internalization of a payload bound to p32 into the cytoplasm. We also show that nardilysin, a protease capable of cleaving CGKRK, plays a role in the internalization of a p32-bound payload. As p32 is overexpressed and surface displayed in breast cancers, we studied the efficacy of the nanosystem in this cancer. We show highly significant treatment results in an orthotopic model of breast cancer. The specificity of cell surface p32 for tumor-associated cells, its ability to carry payloads to mitochondria, and the efficacy of the system in important types of cancer make the nanosystem a promising candidate for further development.
AB - Antiangiogenic therapy is a promising new treatment modality for cancer, but it generally produces only transient tumor regression. We have previously devised a tumor-targeted nanosystem, in which a pentapeptide, CGKRK, delivers a proapoptotic peptide into the mitochondria of tumor blood vessel endothelial cells and tumor cells. The treatment was highly effective in glioblastoma mouse models completely refractory to other antiangiogenic treatments. Here, we identify p32/gC1qR/HABP, a mitochondrial protein that is also expressed at the cell surface of activated (angiogenic) endothelial cells and tumor cells, as a receptor for the CGKRK peptide. The results demonstrate the ability of p32 to cause internalization of a payload bound to p32 into the cytoplasm. We also show that nardilysin, a protease capable of cleaving CGKRK, plays a role in the internalization of a p32-bound payload. As p32 is overexpressed and surface displayed in breast cancers, we studied the efficacy of the nanosystem in this cancer. We show highly significant treatment results in an orthotopic model of breast cancer. The specificity of cell surface p32 for tumor-associated cells, its ability to carry payloads to mitochondria, and the efficacy of the system in important types of cancer make the nanosystem a promising candidate for further development.
UR - http://www.scopus.com/inward/record.url?scp=84890127228&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/mt.2013.191
DO - https://doi.org/10.1038/mt.2013.191
M3 - مقالة
C2 - 23959073
SN - 1525-0016
VL - 21
SP - 2195
EP - 2204
JO - Molecular Therapy
JF - Molecular Therapy
IS - 12
ER -
