title: Systemic GLIPR1-ΔTM protein as a novel therapeutic approach for prostate cancer.
abstract: GLIPR1 is a p53 target gene known to be downregulated in prostate cancer, and increased endogenous GLIPR1 expression has been associated with increased production of reactive oxygen species, increased apoptosis, decreased c-Myc protein levels and increased cell cycle arrest. Recently, we found that upregulation of GLIPR1 in prostate cancer cells increases mitotic catastrophe through interaction with heat shock cognate protein 70 (Hsc70) and downregulation of Aurora kinase A and TPX2. In this study, we evaluated the mechanisms of recombinant GLIPR1 protein (glioma pathogenesis-related protein 1-transmembrane domain deleted [GLIPR1-ΔTM]) uptake by prostate cancer cells and the efficacy of systemic GLIPR1-ΔTM administration in a prostate cancer xenograft mouse model. GLIPR1-ΔTM was selectively internalized by prostate cancer cells, leading to increased apoptosis through reactive oxygen species production and to decreased c-Myc protein levels. Interestingly, GLIPR1-ΔTM was internalized through clathrin-mediated endocytosis in association with Hsc70. Systemic administration of GLIPR1-ΔTM significantly inhibited VCaP xenograft growth. GLIPR1-ΔTM showed no evidence of toxicity following elimination from mouse models 8 hr after injection. Our results demonstrate that GLIPR1-ΔTM is selectively endocytosed by prostate cancer cells, leading to increased reactive oxygen species production and apoptosis, and that systemic GLIPR1-ΔTM significantly inhibits growth of VCaP xenografts without substantial toxicity.
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Karantanos
authors.forename: Ryuta
authors.initials: R
authors.lastname: Tanimoto
authors.forename: Kohei
authors.initials: K
authors.lastname: Edamura
authors.forename: Takahiro
authors.initials: T
authors.lastname: Hirayama
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Alexei A
authors.initials: AA
authors.lastname: Golstov
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Wang
authors.forename: Shinji
authors.initials: S
authors.lastname: Kurosaka
authors.forename: Sanghee
authors.initials: S
authors.lastname: Park
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Thompson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002966:Clathrin / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects / Q000235:genetics; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017384:Sequence Deletion / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D002966:Clathrin; C094538:GLIPR1 protein, human; C489427:MYC protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species
keywords: GLIPR1; prostate cancer; protein therapy