Activation of Akt and ERK signalling pathways induced by etoposide confer chemoresistance in gastric cancer cells

Dig Liver Dis. 2006 May;38(5):310-8. doi: 10.1016/j.dld.2006.01.012. Epub 2006 Mar 9.


Aims: To identify whether phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase/extracellular-regulated protein kinases signalling pathways are implicated in the chemoresistance of gastric cancer and to explore the possible mechanisms.

Methods: Gastric cancer cell lines SGC7901 and BGC823 were exposed to etoposide, Wortmannin+etoposide or PD98059+etoposide. Cell cycle distribution and cell apoptosis were detected using flow cytometry and Hoechst 33258 staining. Cells viability was determined by a colourimetric assay utilising 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT). Akt activity was detected using non-radioactive immunoprecipitation-kinase assay. Western blotting was exploited to evaluate the level of phosphorylated ERK1/2 and expressions of c-Myc and p53 protein.

Results: Etoposide suppressed the viability of SGC7901 and BGC823 cells in a time- and dose-dependent manner; PD98059 and Wortmannin were able to enhance the cytotoxicity of etoposide. The apoptotic levels of cells treated with Wortmannin+etoposide or PD98059+etoposide were significantly higher than those of cells treated with etoposide only. Phospho-ERK1/2, Akt activity and expression of c-Myc were significantly induced by etoposide in a time-dependent manner; moreover, there was a weak effect on the expression of p53 protein. Both Wortmannin and PD98059 elevated the level of p53 expression strikingly, however, only PD98059 suppressed the up-regulation trend of c-Myc expression induced by etoposide.

Conclusion: Chemotherapy reagent activated phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase/extracellular-regulated protein kinases signalling pathways, which decreased the chemotherapy sensitivity of gastric cancer cell lines SGC7901 and BGC823 via suppressing the expression of p53 and enhancing the expression of c-Myc. This may be one of the molecular mechanisms of gastric cancer chemoresistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / physiology*
  • Enzyme Activation / drug effects
  • Etoposide / pharmacology*
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Flavonoids / pharmacology
  • Humans
  • MAP Kinase Signaling System / drug effects*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • Wortmannin


  • Androstadienes
  • Antineoplastic Agents, Phytogenic
  • Flavonoids
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-myc
  • Tumor Suppressor Protein p53
  • Etoposide
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
  • Wortmannin