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.

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
  • 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
  • cdc25 Phosphatases* / genetics
  • cdc25 Phosphatases* / metabolism

Substances

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

Supplementary concepts

  • Pancreatic Carcinoma