TY - JOUR
T1 - Hsp90 stabilizes Cdc25A and counteracts heat shock-mediated Cdc25A degradation and cell-cycle attenuation in pancreatic carcinoma cells
AU - Giessrigl, Benedikt
AU - Krieger, Sigurd
AU - Rosner, Margit
AU - Huttary, Nicole
AU - Saiko, Philipp
AU - Alami, Mouad
AU - Messaoudi, Samir
AU - Peyrat, Jean François
AU - Maciuk, Alexandre
AU - Gollinger, Michaela
AU - Kopf, Sabine
AU - Kazlauskas, Egidijus
AU - Mazal, Peter
AU - Szekeres, Thomas
AU - Hengstschläger, Markus
AU - Matulis, Daumantas
AU - Jäger, Walter
AU - Krupitza, Georg
PY - 2012/11/1
Y1 - 2012/11/1
N2 - Pancreas cancer cells escape most treatment options. Heat shock protein (Hsp)90 is frequently over-expressed in pancreas carcinomas and protects a number of cell-cycle regulators such as the proto-oncogene Cdc25A. We show that inhibition of Hsp90 with geldanamycin (GD) destabilizes Cdc25A independent of Chk1/2, whereas the standard drug for pancreas carcinoma treatment, gemcitabine (GEM), causes Cdc25A degradation through the activation of Chk2. Both agents applied together additively inhibit the expression of Cdc25A and the proliferation of pancreas carcinoma cells thereby demonstrating that both Cdc25A-destabilizing/degrading pathways are separated. The role of Hsp90 as stabilizer of Cdc25A in pancreas carcinoma cells is further supported by two novel synthetic inhibitors 4-tosylcyclonovobiocic acid and 7-tosylcyclonovobiocic acid and specific Hsp90AB1 (Hsp90β) shRNA. Our data show that targeting Hsp90 reduced the resistance of pancreas carcinoma cells to treatment with GEM.
AB - Pancreas cancer cells escape most treatment options. Heat shock protein (Hsp)90 is frequently over-expressed in pancreas carcinomas and protects a number of cell-cycle regulators such as the proto-oncogene Cdc25A. We show that inhibition of Hsp90 with geldanamycin (GD) destabilizes Cdc25A independent of Chk1/2, whereas the standard drug for pancreas carcinoma treatment, gemcitabine (GEM), causes Cdc25A degradation through the activation of Chk2. Both agents applied together additively inhibit the expression of Cdc25A and the proliferation of pancreas carcinoma cells thereby demonstrating that both Cdc25A-destabilizing/degrading pathways are separated. The role of Hsp90 as stabilizer of Cdc25A in pancreas carcinoma cells is further supported by two novel synthetic inhibitors 4-tosylcyclonovobiocic acid and 7-tosylcyclonovobiocic acid and specific Hsp90AB1 (Hsp90β) shRNA. Our data show that targeting Hsp90 reduced the resistance of pancreas carcinoma cells to treatment with GEM.
U2 - 10.1093/hmg/dds303
DO - 10.1093/hmg/dds303
M3 - Article
C2 - 22843495
AN - SCOPUS:84867803881
SN - 0964-6906
VL - 21
SP - 4615
EP - 4627
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 21
M1 - dds303
ER -
