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

Theodoros Karantanos, Ryuta Tanimoto, Kohei Edamura, Takahiro Hirayama, Guang Yang, Alexei A. Golstov, Jianxiang Wang, Shinji Kurosaka, Sanghee Park, Timothy C. Thompson

Research output: Contribution to journalArticle

5 Citations (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)2003-2013
Number of pages11
JournalInternational Journal of Cancer
Volume134
Issue number8
DOIs
Publication statusPublished - Apr 15 2014

Keywords

  • GLIPR1
  • prostate cancer
  • protein therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Systemic GLIPR1-ΔTM protein as a novel therapeutic approach for prostate cancer'. Together they form a unique fingerprint.

  • Cite this

    Karantanos, T., Tanimoto, R., Edamura, K., Hirayama, T., Yang, G., Golstov, A. A., Wang, J., Kurosaka, S., Park, S., & Thompson, T. C. (2014). Systemic GLIPR1-ΔTM protein as a novel therapeutic approach for prostate cancer. International Journal of Cancer, 134(8), 2003-2013. https://doi.org/10.1002/ijc.28529