Abstract
The heat shock protein (HSP) 90 chaperone machine involved in numerous oncogenic signaling pathways is overexpressed in cancer cells and is currently being evaluated for anticancer therapy. Neuroendocrine tumors (NETs) of the gastroenteropancreatic (GEP) system comprise a heterogeneous group of tumors with increasing incidence and poor prognosis. Here, we report the antiproliferative effects of the HSP90 inhibitors AUY922 and HSP990 in neuroendocrine tumor cells. Treatment of human pancreatic BON1, bronchopulmonary NCI-H727 and midgut carcinoid GOT1 neuroendocrine tumor cells with increasing concentrations of AUY922 and HSP990 dose-dependently suppressed cell viability. Significant effects on neuroendocrine cell viability were observed with inhibitor concentrations as low as 5 nM. Inhibition of cell viability was associated with the induction of apoptosis as demonstrated by an increase in sub-G1 events and PARP cleavage. HSP90 inhibition was associated with decreased neuroendocrine ErbB and IGF-I receptor expression, decreased Erk and Akt phospho-rylation and the induction of HSP70 expression. These findings provide evidence that targeted inhibition of upregulated HSP90 activity could be useful for the treatment of aggressive neuroendocrine tumors resistant to conventional therapy.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing / metabolism
-
Apoptosis / drug effects
-
Carcinoid Tumor / drug therapy*
-
Carcinoma, Neuroendocrine / drug therapy*
-
Carcinoma, Neuroendocrine / metabolism
-
Cell Cycle Proteins
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
Cell Survival / drug effects
-
Extracellular Signal-Regulated MAP Kinases / metabolism
-
HSP70 Heat-Shock Proteins / biosynthesis
-
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
-
Humans
-
Isoxazoles / pharmacology*
-
Lung Neoplasms / drug therapy
-
M Phase Cell Cycle Checkpoints / drug effects
-
Pancreatic Neoplasms / drug therapy
-
Phosphoproteins / metabolism
-
Phosphorylation / drug effects
-
Poly(ADP-ribose) Polymerases / metabolism
-
Proto-Oncogene Proteins c-akt / metabolism
-
Pyridones / pharmacology*
-
Pyrimidines / pharmacology*
-
Receptor, ErbB-2 / biosynthesis
-
Receptor, IGF Type 1 / biosynthesis
-
Resorcinols / pharmacology*
-
Ribosomal Protein S6 Kinases, 70-kDa / metabolism
-
Signal Transduction / drug effects
Substances
-
2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido(4,3-d)pyrimidin-5(6H)-one
-
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
-
Adaptor Proteins, Signal Transducing
-
Cell Cycle Proteins
-
EIF4EBP1 protein, human
-
HSP70 Heat-Shock Proteins
-
HSP90 Heat-Shock Proteins
-
Isoxazoles
-
Phosphoproteins
-
Pyridones
-
Pyrimidines
-
Resorcinols
-
Poly(ADP-ribose) Polymerases
-
ERBB2 protein, human
-
Receptor, ErbB-2
-
Receptor, IGF Type 1
-
Proto-Oncogene Proteins c-akt
-
Ribosomal Protein S6 Kinases, 70-kDa
-
Extracellular Signal-Regulated MAP Kinases