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Volume 17, Number 2, Issue of January 15, 1997 pp. 530-542
Copyright ©1997 Society for Neuroscience

Nerve Growth Factor Induces Apoptosis in Human Medulloblastoma Cell Lines that Express TrkA Receptors

Received Aug. 9, 1996; revised Oct. 17, 1996; accepted Oct. 23, 1996.

Yoshihiro Muragaki^{1, 2}, Thomas T. Chou¹, David R. Kaplan³, John Q. Trojanowski¹, and Virginia M.-Y. Lee¹

¹ Department of Pathology and Laboratory Medicine, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4283, ² Department of Neurosurgery, Tokyo Women's Medical College, Tokyo, Japan, and ³ The ABL-Basic Research Program, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland 21702

Neurotrophins act through their cognate receptors to promote the differentiation and/or survival of neuronal progenitor cells, immature neurons, and other cells. Here, we examined the effects of nerve growth factor (NGF) and its cognate receptor (Trk or TrkA) on the survival of a common childhood brain tumor, i.e., medulloblastoma, a tumor that resembles CNS neuroepithelial progenitor cells. To do this, we engineered two human medulloblastoma cell lines (i.e., D283MED and DAOY cells) to express human TrkA using a retroviral expression vector. Surprisingly, NGF-treated medulloblastoma cells expressing the TrkA receptor (D283trk and DAOYtrk cells) grown in the presence or absence of serum underwent massive apoptosis, but similar treatment did not induce apoptosis in wild-type uninfected cells, cells expressing an empty vector, or cells expressing the TrkC receptor. Furthermore, D283MED cells engineered to express the human p75 NGF receptor (D283p75) also did not undergo apoptosis. Significantly, NGF-induced apoptosis in D283trk and DAOYtrk cells can be inhibited by anti-NGF antibodies and by K-252a, an inhibitor of TrkA tyrosine phosphorylation and mimicked by high concentrations of NT3. Because NGF treatment primarily eliminated D283trk cells from the S phase of the cell cycle, this form of NGF-mediated apoptosis is cell cycle-dependent. These findings suggest that a NGF/TrkA signal transduction pathway could activate apoptotic cell death programs in CNS neuroepithelial progenitor cells and in childhood brain tumors.

Key words: nerve growth factor; neurotrophins; medulloblastoma; TrkA; apoptosis; S phase

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