Glioma pathogenesis-related protein 1: tumor-suppressor activities and therapeutic potential.
After glioma pathogenesis-related protein 1 (GLIPR1/Glipr1) was identified, the expression of GLIPR1 was shown to be down-regulated in human prostate cancer, owing in part to methylation in the regulatory region of this gene in prostate cancer cells. Additional studies showed that GLIPR1/Glipr1 expression is induced by DNA-damaging agents independent of p53. Functional analysis of GLIPR1 using in vitro and in vivo gene-transfer approaches revealed both growth suppression and proapoptotic activities for mouse Glipr1 and human GLIPR1 in multiple cancer cell lines. The proapoptotic activities were dependent on production of reactive oxygen species and sustained c-Jun-NH(2) kinase signaling. It was interesting that adenoviral vector-mediated Glipr1 (AdGlipr1) transduction into prostate cancer tissues using an immunocompetent orthotopic mouse model revealed additional biologic activities consistent with tumor-suppressor functions. Significantly reduced tumor-associated angiogenesis and direct suppression of endothelial-cell sprouting activities were documented. In addition, AdGlipr1 strongly stimulated antitumor immune responses that resulted in specific cytotoxic T-lymphocyte activities in this model. Glipr1-related antitumor immunostimulatory activities were confirmed and extended in subsequent studies. Administration of a novel Glipr1 genemodified tumor cell vaccine had significant antitumor activity in a mouse model of recurrent prostate cancer. In conclusion, restoration of GLIPR1 function in prostate cancer cells through GLIPR1 gene-based or GLIPR protein-based delivery methods may provide a safe and effective approach for targeted therapy for a range of malignancies.
Thompson
Timothy C
TC
Department of Genitourinary Medical Oncology-Research, Unit 18-3, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA. timthomp@mdanderson.org
D000818:Animals; D017209:Apoptosis; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000628:therapy*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000502:physiology*
C094538:GLIPR1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D025521:Tumor Suppressor Proteins