Nerve growth factor regulates neuroectodermal tumor cell responses to mitogenic growth factors.
Previous studies showed that nerve growth factor (NGF) decreases the proliferation of neuroectodermal tumor (NET) cells (C-1300 and Neuro2A murine neuroblastoma, PC12 rat pheochromocytoma) within 5-7 days in a dose-dependent manner. This effect is regulated by the concentration of serum in the culture medium. Therefore, we hypothesized that NGF exerts its antimitogenic activities by interfering with the proliferative action of other growth factors. We studied the effects of short-term vs. long-term as well as endogenous vs. exogenous NGF on NET cell proliferation in response to various mitogenic growth factors. Retrovirus-mediated transfer of the beta-NGF gene into NET cells activated TrkA and consistently decreased their proliferative responses to insulin-like growth factor (IGF)-I, IGF-II, fibroblast growth factor-2, and epidermal growth factor (EGF), down-regulating EGF and IGF-I binding sites. It also decreased tyrosine phosphorylation of ERK-1, STAT3, and EGF or IGF receptors after treatment with IGF-I or EGF. Long-term incubation of NET cells with NGF mimicked the responses induced by beta-NGF gene transfer, albeit in a reversible manner. Short-term NGF treatment augmented the proliferative responses to IGF-I or EGF by enhancing cell survival. It also increased tyrosine phosphorylation of signal transducing proteins after exposure to IGF or EGF, an effect opposite to that of long-term NGF treatments. Hence, long-term NGF exposure in vitro might better reproduce the effects of NGF in vivo than short-term treatments. Only long-term exposure to NGF decreased the responses of NET cells to mitogenic growth factors by down-regulating their receptors and attenuating signal transduction events required for cell proliferation. These results suggest that NGF could exert similar actions on cellular responses to growth factors in vivo.
Castellon
Raquel
R
Department of Ophthalmology, University of California Irvine, USA. rcastell@uci.edu
Mirkin
Bernard L
BL
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006133:Growth Substances / Q000378:metabolism; D051379:Mice; D008934:Mitogens / Q000378:metabolism; D020932:Nerve Growth Factor / Q000008:administration & dosage / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism; D017599:Neuroectodermal Tumors / Q000378:metabolism*; D016716:PC12 Cells / Q000378:metabolism; D051381:Rats; D017978:Receptors, Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D006133:Growth Substances; D008934:Mitogens; D017978:Receptors, Growth Factor; D020932:Nerve Growth Factor