Inhibition of PI3K/Akt partially leads to the inhibition of PrP(C)-induced drug resistance in gastric cancer cells

FEBS J. 2009 Feb;276(3):685-94. doi: 10.1111/j.1742-4658.2008.06816.x.


Cellular prion protein (PrP(C)), a glycosyl-phosphatidylinositol-anchored membrane protein with unclear physiological function, was previous found to be upregulated in adriamycin (ADR)-resistant gastric carcinoma cell line SGC7901/ADR compared to its parental cell line SGC7901. Overexpression of PrP(C) in gastric cancer has certain effects on drug accumulation through upregulation of P-glycoprotein (P-gp), which is suggested to play an important role in determining the sensitivity of tumor cells to chemotherapy and is linked to activation of the phosphatidylinositol-3-kinase/Akt (PI3K/Akt) pathway. In the present study, we further investigate the role of the PI3K/Akt pathway in PrP(C)-induced multidrug-resistance (MDR) in gastric cancer. Immunohistochemistry and confocal microscope detection suggest a positive correlation between PrP(C) and phosphorylated Akt (p-Akt) expression in gastric cancer. Using established stable PrP(C) transfectant cell lines, we demonstrated that the level of p-Akt was increased in PrP(C)-transfected cells. Inhibition of PrP(C) expression by RNA interference resulted in decreased p-Akt expression. Inhibition of the PI3K/Akt pathway by one of its specific inhibitors, LY294002, or by Akt small interfering RNA (siRNA) resulted in decreased multidrug resistance of SGC7901 cells, partly through downregulation of P-gp induced by PrP(C). Taken together, our results suggest that PrP(C)-induced MDR in gastric cancer is associated with activation of the PI3K/Akt pathway. Inhibition of PI3K/Akt by LY2940002 or Akt siRNA leads to inhibition of PrP(C)-induced drug resistance and P-gp upregulation in gastric cancer cells, indicating a possible novel mechanism by which PrP(C) regulates gastric cancer cell survival.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Adult
  • Aged
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm*
  • Enzyme Activation
  • Female
  • Humans
  • Inhibitory Concentration 50
  • Male
  • Middle Aged
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Prions / genetics
  • Prions / metabolism*
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / pathology*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Phosphoinositide-3 Kinase Inhibitors
  • Prions
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt