title: Hsp90 stabilizes Cdc25A and counteracts heat shock-mediated Cdc25A degradation and cell-cycle attenuation in pancreatic carcinoma cells.
abstract: 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.
authors: 1Institute of Clinical Pathology, Medical University of Vienna, General Hospital of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria.
authors: Benedikt
authors: B
authors: Giessrigl
authors: Sigurd
authors: S
authors: Krieger
authors: Margit
authors: M
authors: Rosner
authors: Nicole
authors: N
authors: Huttary
authors: Philipp
authors: P
authors: Saiko
authors: Mouad
authors: M
authors: Alami
authors: Samir
authors: S
authors: Messaoudi
authors: Jean-François
authors: JF
authors: Peyrat
authors: Alexandre
authors: A
authors: Maciuk
authors: Michaela
authors: M
authors: Gollinger
authors: Sabine
authors: S
authors: Kopf
authors: Egidijus
authors: E
authors: Kazlauskas
authors: Peter
authors: P
authors: Mazal
authors: Thomas
authors: T
authors: Szekeres
authors: Markus
authors: M
authors: Hengstschläger
authors: Daumantas
authors: D
authors: Matulis
authors: Walter
authors: W
authors: Jäger
authors: Georg
authors: G
authors: Krupitza
mesh_terms: D016227:Benzoquinones / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D009675:Novobiocin / Q000031:analogs & derivatives / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: C535075:4-tosylcyclonovobiocic acid; C535076:7-tosylcyclonovobiocic acid; D016227:Benzoquinones; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D003841:Deoxycytidine; D009675:Novobiocin; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases; C001277:geldanamycin; D000093542:Gemcitabine