Hsp90 stabilizes Cdc25A and counteracts heat shock-mediated Cdc25A degradation and cell-cycle attenuation in pancreatic carcinoma cells

Benedikt Giessrigl; Sigurd Krieger; Margit Rosner; Nicole Huttary; Philipp Saiko; Mouad Alami; Samir Messaoudi; Jean-François Peyrat; Alexandre Maciuk; Michaela Gollinger; Sabine Kopf; Egidijus Kazlauskas; Peter Mazal; Thomas Szekeres; Markus Hengstschläger; Daumantas Matulis; Walter Jäger; Georg Krupitza

doi:10.1093/hmg/dds303

Hsp90 stabilizes Cdc25A and counteracts heat shock-mediated Cdc25A degradation and cell-cycle attenuation in pancreatic carcinoma cells

Hum Mol Genet. 2012 Nov 1;21(21):4615-27. doi: 10.1093/hmg/dds303. Epub 2012 Jul 25.

Authors

Benedikt Giessrigl¹, Sigurd Krieger, Margit Rosner, Nicole Huttary, Philipp Saiko, Mouad Alami, Samir Messaoudi, Jean-François Peyrat, Alexandre Maciuk, Michaela Gollinger, Sabine Kopf, Egidijus Kazlauskas, Peter Mazal, Thomas Szekeres, Markus Hengstschläger, Daumantas Matulis, Walter Jäger, Georg Krupitza

Affiliation

¹ 1Institute of Clinical Pathology, Medical University of Vienna, General Hospital of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria.

PMID: 22843495
DOI: 10.1093/hmg/dds303

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Benzoquinones / pharmacology
Cell Cycle Proteins* / drug effects
Cell Cycle Proteins* / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Checkpoint Kinase 1
Checkpoint Kinase 2
Deoxycytidine / analogs & derivatives
Deoxycytidine / pharmacology
Gemcitabine
Gene Expression Regulation, Neoplastic / drug effects*
HSP90 Heat-Shock Proteins* / antagonists & inhibitors
HSP90 Heat-Shock Proteins* / metabolism
Humans
Lactams, Macrocyclic / pharmacology
Novobiocin / analogs & derivatives
Novobiocin / pharmacology
Pancreatic Neoplasms* / genetics
Pancreatic Neoplasms* / metabolism
Protein Kinases / metabolism
Protein Serine-Threonine Kinases / metabolism
Proteolysis / drug effects
Proto-Oncogene Mas
cdc25 Phosphatases* / genetics
cdc25 Phosphatases* / metabolism

Substances

4-tosylcyclonovobiocic acid
7-tosylcyclonovobiocic acid
Benzoquinones
Cell Cycle Proteins
HSP90 Heat-Shock Proteins
Lactams, Macrocyclic
MAS1 protein, human
Proto-Oncogene Mas
Deoxycytidine
Novobiocin
Protein Kinases
Checkpoint Kinase 2
CHEK1 protein, human
CHEK2 protein, human
Checkpoint Kinase 1
Protein Serine-Threonine Kinases
CDC25A protein, human
cdc25 Phosphatases
geldanamycin
Gemcitabine