Discordant effects of rapamycin on proliferation and p70S6 kinase phosphorylation in normal and neoplastic rat chromaffin cells

Normal adult rat chromaffin cells show a robust proliferative response in v itro to nerve growth factor (NGF) and other mitogens. In contrast, PC12 rat pheochromocytoma cells proliferate in the absence of exogenous mitogens an d undergo neuronal differentiation in response to NGF. We demonstrate in th is work that the antiproliferative drug rapamycin suppresses normal chromaf fin cell proliferation. This effect is blocked by FK 506, indicating that i t occurs via interaction of rapamycin with its intracellular binding protei n, FKBP. Rapamycin must be added within 2 days of mitogen stimulation in or der to be fully effective. PC12 cells are refractory to the antiproliferati ve effect of rapamycin, although rapamycin does exert its expected inhibito ry effect in PC12 cells on both basal and NGF-stimulated activation of one of its biochemical targets, the 70-kDa S6 protein kinase (p70S6K). The disc ordant findings suggest that a proliferative signal normally requiring acti vation of p70S6K either is unnecessary in PC12 cells or is provided by a do wnstream or cross-communicating pathway. They also suggest that p70S6K does not participate in the morphological responses of PC12 cells to NGF. Deter mining the basis for rapamycin resistance in PC12 cells might help to ident ify signaling abnormalities involved in the pathogenesis of pheochromocytom a. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.