title: Proapoptotic peptide-mediated cancer therapy targeted to cell surface p32.
abstract: 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.
authors: 1] Cancer Research Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA [2] Center for Nanomedicine and Department of Cell, Molecular and Developmental Biology, University of California, Santa Barbara, California, USA.
authors: Lilach
authors: L
authors: Agemy
authors: Venkata R
authors: VR
authors: Kotamraju
authors: Dinorah
authors: D
authors: Friedmann-Morvinski
authors: Shweta
authors: S
authors: Sharma
authors: Kazuki N
authors: KN
authors: Sugahara
authors: Erkki
authors: E
authors: Ruoslahti
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008325:Mammary Neoplasms, Experimental; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D053758:Nanoparticles / Q000737:chemistry*; D009928:Organ Specificity; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011951:Receptors, Complement / Q000235:genetics / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D008562:Membrane Glycoproteins; D024101:Mitochondrial Proteins; D010455:Peptides; D011951:Receptors, Complement; C032402:complement 1q receptor; D008666:Metalloendopeptidases; C087976:nardilysin
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