Opposite effects of the Hsp90 inhibitor Geldanamycin: induction of apoptosis in PC12, and differentiation in N2A cells

• Published in: FEBS letters 2001-02, Vol.490 (1), p.23-27
• Main Authors: López-Maderuelo, M.Dolores, Fernández-Renart, Margarita, Moratilla, Carmen, Renart, Jaime
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - pharmacology; Apoptosis; Apoptosis - drug effects; Benzoquinones; Cell Differentiation - drug effects; Differentiation; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; ERK, extracellular signal-regulated kinase; GA, Geldanamycin; Geldanamycin; HSP90 Heat-Shock Proteins - antagonists & inhibitors; Imidazoles - pharmacology; JNK Mitogen-Activated Protein Kinases; JNK, c-jun N-terminal kinase; Kinetics; Lactams, Macrocyclic; MAP Kinase Signaling System - drug effects; MAPK, mitogen-activated protein kinase; MBP, myelin basic protein; Mice; Mitogen-activated protein kinase; Mitogen-Activated Protein Kinases - metabolism; Nerve Growth Factor - metabolism; Neuroblastoma - metabolism; NGF, nerve growth factor; PC12 Cells; Phenotype; PI3K, phosphatidylinositol-3′-kinase; PP2, 4-amino-5-(4-chlorophenyl)-7-(tbutyl)pyrazolo[3,4-d]pyrimidine; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins c-raf - metabolism; Proto-Oncogene Proteins pp60(c-src) - metabolism; Pyridines - pharmacology; Quinones - pharmacology; Raf-1; Rats; Time Factors; Tumor Cells, Cultured
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/S0014-5793(01)02130-5

The inhibitor of the Hsp90 chaperone Geldanamycin has been reported to have several cellular effects, such as inhibition of v-src activity or destabilization of Raf-1 among others. We show now that Geldanamycin treatment induces different phenotypes in different cell lines. In PC12 cells, it triggers apoptosis, whereas in the murine neuroblastoma N2A, it induces differentiation with neurite outgrowth. Geldanamycin effects cannot be mimicked by inhibition of the c-src protein tyrosine kinases, and nerve growth factor does not protect PC12 cells from apoptosis. Mitogen-activated protein kinase activities ERK and JNK are activated differently according to cell type: in PC12 cells JNK is activated, and its inhibition abolishes apoptosis, but not ERK; in N2A cells, both ERK and JNK are activated, but with peak activities at different times.