tretinoin and geldanamycin

Geldanamycin (GA) is a specific inhibitor of the 90 kDs heat shock protein (Hsp90) in the cytoplasm of mammalian cells, which binds directly to Hsp90 and promotes proteolytic degradation of its client proteins. As an antitumor drug, GA antagonizes the protecting effects of Hsp90 on cell survival, while its mechanisms remain unclear. Here, we show that GA induces apoptosis in a human neuroblastoma cell line, SH-SY5Y. Treatment of the cells with all trans retinoic acid (RA) generates a neuron-like, morphological change of differentiation, and results in the activation of ERK and Akt pathways, an inhibition of the nuclear translocation of p53 induced by GA, and induces higher resistance to the GA-induced apoptosis. These results provide the first evidence for the requirement of p53 nucleation in SH-SY5Y cells to counteract GA in neuron survival.

Topics: Active Transport, Cell Nucleus; Antibiotics, Antineoplastic; Apoptosis; Benzoquinones; Brain Neoplasms; Cell Differentiation; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Ganglia, Sympathetic; Humans; Lactams, Macrocyclic; Neuroblastoma; Neurons; Proto-Oncogene Proteins c-akt; Tretinoin; Tumor Suppressor Protein p53