Systemic GLIPR1-ΔTM protein as a novel therapeutic approach for prostate cancer

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-TM]) uptake by prostate cancer cells and the efficacy of systemic GLIPR1-TM administration in a prostate cancer xenograft mouse model. GLIPR1-TM 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-TM was internalized through clathrin-mediated endocytosis in association with Hsc70. Systemic administration of GLIPR1-TM significantly inhibited VCaP xenograft growth. GLIPR1-TM showed no evidence of toxicity following elimination from mouse models 8 hr after injection. Our results demonstrate that GLIPR1-TM is selectively endocytosed by prostate cancer cells, leading to increased reactive oxygen species production and apoptosis, and that systemic GLIPR1-TM significantly inhibits growth of VCaP xenografts without substantial toxicity.