The “go or grow” potential of gliomas is linked to the neuropeptide processing enzyme carboxypeptidase E and mediated by metabolic stress

• DOI: 10.1007/s00401-011-0940-x
• Publication Date: 2012-01-16T10:58:07Z
• Authors: Elisabeth Höring; Patrick Nikolaus ...; Janina Seznec; Jens Schittenhelm; Hans-Jörg Bühring; Shohag Bhattacharyya; Elke von Hattingen; Cornelia Zachskorn; Michel Mittelbronn; Ulrike Naumann
• Keywords: 0303 health sciences; Brain Neoplasms; Carboxypeptidase H; Glioma; Carbocyanines; Cell Hypoxia; 3. Good health; Gene Expression Regulation, Neoplastic; Mice, Inbred C57BL; Disease Models, Animal; Mice; 03 medical and health sciences; Glucose; Cell Movement; Cell Line, Tumor; Glial Fibrillary Acidic Protein; Cell Adhesion; Animals; Humans; Neoplasm Invasiveness; RNA, Messenger; RNA, Small Interfering; Cell Proliferation

Glioblastoma (GBM), the most common malignant brain tumor, is among the most lethal neoplasms, with a median survival of approximately 1 year. Prognosis is poor since GBMs possess a strong migratory and highly invasive potential, making complete surgical resection impossible. Reduced expression of carboxypeptidase E (CPE), a neuropeptide-processing enzyme, in a cell death-resistant glioma cell line and lower CPE expression levels in the cohort of GBM samples of The Cancer Genome Atlas compared to normal brain control specimens prompted us to analyze the function of CPE as a putative tumor suppressor gene. In our samples, CPE was also reduced in GBM compared to normal brain with the strongest loss in cells surrounding hypoxic tumor areas as well as in most glioma cell lines and primary glioma cells. In our cohort of glioma patients, loss of CPE predominantly occurred in glioblastomas and was associated with worse prognosis. In glioma cells, CPE overexpression was significantly reduced, whereas knockdown or inhibition enhanced glioma cell migration and invasion. The decreased migratory potential following CPE overexpression was paralleled by altered cellular morphology, promoting a transition to focal adhesions and associated stress fibers. In contrast to the decreased migration, high CPE levels were associated with higher proliferative rates. As microenvironmental regulation cues, we identified CPE as being downregulated upon hypoxia or glucose deprivation. Our findings indicate an oxygen- and nutrition-dependent anti-migratory, but pro-proliferative role of CPE in gliomas with prognostic impact for patient survival, thereby contributing to the understanding of the "go or grow" hypothesis in gliomas.