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

• Published in: International journal of cancer 2014-04, Vol.134 (8), p.2003-2013
• Main Authors: Karantanos, Theodoros, Tanimoto, Ryuta, Edamura, Kohei, Hirayama, Takahiro, Yang, Guang, Golstov, Alexei A., Wang, Jianxiang, Kurosaka, Shinji, Park, Sanghee, Thompson, Timothy C.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Apoptosis - genetics; Biological and medical sciences; Cell Cycle Checkpoints - genetics; Cell Line, Tumor; Cell Survival - genetics; Clathrin - metabolism; Endocytosis - drug effects; Endocytosis - genetics; Endosomes - metabolism; GLIPR1; Humans; Lysosomes - metabolism; Male; Medical sciences; Mice; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasm Proteins - therapeutic use; Neoplasm Transplantation; Nephrology. Urinary tract diseases; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nerve Tissue Proteins - therapeutic use; prostate cancer; Prostatic Neoplasms - drug therapy; protein therapy; Protein Transport - drug effects; Protein Transport - genetics; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Reactive Oxygen Species - metabolism; Sequence Deletion - genetics; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Xenograft Model Antitumor Assays
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.28529

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. What's new? Downregulation of the p53 target gene GLIPR1 in multiple types of human cancer has prompted the development and exploration of an antitumor recombinant GLIPR1 protein (GLIPR1‐ΔΤΜ). The present study demonstrates that GLIPR1‐ΔΤΜ is selectively taken up by cancerous prostate cells, where it employs the same mechanisms of action as those used by endogenous GLIPR1, including reactive oxygen species‐mediated apoptosis, downregulation of c‐Myc, and interaction with Hsc70. Systemic GLIPR1‐ΔΤΜ inhibited overall tumor growth and had rapid clearance and limited toxicity in mouse models. The findings warrant further study of GLIPR1‐ΔΤΜ as a neoadjuvant therapy for prostate cancer.