Zhangfei induces the expression of the nerve growth factor receptor, trkA, in medulloblastoma cells and causes their differentiation or apoptosis

• Published in: Journal of neuro-oncology 2009, Vol.91 (1), p.7-17
• Main Authors: Valderrama, Ximena, Rapin, Noreen, Verge, Valerie M. K., Misra, Vikram
• Format: Article
• Language: English
• Subjects: Adenovirus; Angiogenesis Inhibitors - pharmacology; Animals; Apoptosis - drug effects; Apoptosis - physiology; Basic-Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors - metabolism; Basic-Leucine Zipper Transcription Factors - pharmacology; Caspase 3 - pharmacology; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cell Line, Tumor; Cell Proliferation - drug effects; Early Growth Response Protein 1 - genetics; Early Growth Response Protein 1 - metabolism; Flow Cytometry - methods; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - physiology; Humans; Laboratory Investigation- Human/Animal Tissue; Medicine; Medicine & Public Health; Medulloblastoma - genetics; Medulloblastoma - metabolism; Neurology; Oncology; PC12 Cells; Rats; Receptor, Nerve Growth Factor - genetics; Receptor, Nerve Growth Factor - metabolism; Receptor, trkA - genetics; Receptor, trkA - metabolism; Stilbenes - pharmacology; Time Factors; Transfection
• ISSN: 0167-594X; 1573-7373
• DOI: 10.1007/s11060-008-9682-6

Interactions between nerve growth factor (NGF) and its receptor—the tropomyosin related kinase A (trkA)—regulate many neuronal functions including the correct development of sensory neurons during embryogenesis, the survival of sensory neurons and the differentiation and apoptosis of neuronal tumours. Zhangfei is a transcriptional factor that is expressed in differentiated neurons. Since we could detect Zhangfei in mature neurons but not in neuronal tumour cells, we hypothesised that ectopic expression of the protein in medulloblastoma cells may induce the differentiation of these cells. We show that in ONS-76 medulloblastoma cells, resveratrol, an inducer of apoptosis and differentiation, increased the expression of Zhangfei, trkA and Early Growth Response Gene 1 (Egr1), a gene normally activated by NGF–trkA signalling. ONS-76 cells stopped growing soon after treatment with resveratrol. While the induction of Zhangfei in resveratrol-treated cells was modest albeit consistent, the infection of actively growing medulloblastoma cells with an adenovirus vector expressing Zhangfei mimicked some of the effects of resveratrol. Ectopically expressed Zhangfei in ONS-76 cells led to the increased expression of trkA and Egr1, phosphorylation of extracellular signal-regulated kinase (Erk1), and caused ONS-76 cells to display markers of apoptosis. UW228, another medulloblastoma cell-line, was also susceptible to the suppressive effects of resveratrol and Zhangfei. In contrast, while resveratrol suppressed the growth of human diploid fibroblasts (MRC5), Zhangfei had relatively little effect on these cells.