Mitogen-activated protein kinases and chemoresistance in pancreatic cancer cells

J Surg Res. 2006 Dec;136(2):325-35. doi: 10.1016/j.jss.2006.06.031. Epub 2006 Oct 19.

Abstract

Background: Chemoresistance is an important clinical problem in pancreatic cancer. As the mitogen-activated protein kinases (MAPKs) have been found to be involved in the development of chemoresistance in a variety of cancer cell lines, the aim of the current study was to assess the role and mechanism of MAPK signaling in mediating chemoresistance in pancreatic cancer cells.

Materials and methods: The effects of pharmacological inhibition of MAPKs on resistance of pancreatic cancer cells to apoptosis induced by treatment with chemotherapeutic drugs were analyzed.

Results: Compared with parental cells, the activity of extracellular signal-regulated kinase (ERK) was elevated in all of the three chemoresistant sublines at basal conditions. Inhibition of the ERK pathway by PD98059 sensitized cells to 5-fluorouracil (5-FU), whereas cells became more resistant to Adriamycin (ADM; Meiji Seika, Tokyo, Japan) and gemcitabine (GEM). 5-FU induced apoptosis primarily via a caspase-8-dependent pathway, and ADM and GEM via caspase-9. PD98059 enhanced the activity of caspase-8 and inhibited the activation of caspase-9. In addition, PD98059 regulated the level of phospho-Bcl-2.

Conclusions: These data suggest that although constitutive activation of the ERK pathway might be a marker of chemoresistance, the effects of this pathway on chemoresistance of pancreatic cancer cells are drug dependent. This study also provides evidence for a possible link between the ERK pathway and activation of the caspases and Bcl-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibiotics, Antineoplastic / pharmacology
  • Antimetabolites, Antineoplastic / pharmacology*
  • Apoptosis / drug effects
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Doxorubicin / pharmacology
  • Drug Resistance, Neoplasm / physiology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fluorouracil / pharmacology*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Signaling System / drug effects*
  • Mitogen-Activated Protein Kinases / metabolism
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Antibiotics, Antineoplastic
  • Antimetabolites, Antineoplastic
  • Deoxycytidine
  • Doxorubicin
  • gemcitabine
  • Poly(ADP-ribose) Polymerases
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Fluorouracil