Inhibition of the PI3K-Akt signaling pathway enhances the sensitivity of Fas-mediated apoptosis in human gastric carcinoma cell line, MKN-45

J Cancer Res Clin Oncol. 2004 Jan;130(1):8-14. doi: 10.1007/s00432-003-0505-z. Epub 2003 Nov 7.

Abstract

It is well known that Fas ligand and anti-Fas antibodies can induce apoptosis, although some cancer cells are resistant to their stimuli. On the other hand, phosphatidylinositol 3'-kinase (PI3 K) and Akt mediate the survival signal and allow the cells to escape from apoptosis in various human cancers. Thus, we postulated that LY294002, a PI3 K inhibitor, should inactivate Akt, consequently inhibiting cell proliferation and increase apoptosis in the human gastric carcinoma cell line, MKN-45. Previously, we reported that MKN-45 was resistant against the anti-Fas antibody, CH-11, without interferon-gamma pretreatment in vitro. LY294002 caused a decrease of phosphorylated-Akt and an inhibition of cell proliferation via cell cycle arrest in the G0/G1 phase by P27/Kip1 accumulation, but there was no obvious induction of apoptosis. The simultaneous treatment of LY294002 and CH-11 significantly induced apoptosis confirmed by morphology and DNA ladder formation. Decreased phosphorylated-Akt by LY294002 treatment led to a down-regulation of Mcl-2 and phosphorylated Bad proteins, which are anti-apoptotic factors and belong to the Bcl-2 family. On the other hand, expression levels of the other anti-apoptotic factors, such as FLICE-inhibitory protein (FLIP), Bcl-2 and Bcl-XL, which are associated with the Fas-mediated apoptotic signal pathway, did not change after LY294002 treatment. We concluded that: 1) the PI3K-Akt pathway plays an important role in preventing Fas-mediated apoptosis; and 2) a PI3 K inhibitor, such as LY294002, might be a useful anti-tumoral agent for gastric carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Blotting, Western
  • Carcinoma / drug therapy*
  • Carcinoma / metabolism
  • Cell Line, Tumor
  • Chromones / pharmacology*
  • Enzyme Inhibitors / pharmacology*
  • Fas Ligand Protein
  • Flow Cytometry
  • Humans
  • Membrane Glycoproteins / metabolism
  • Morpholines / pharmacology*
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction / drug effects
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / metabolism

Substances

  • Antineoplastic Agents
  • Chromones
  • Enzyme Inhibitors
  • FASLG protein, human
  • Fas Ligand Protein
  • Membrane Glycoproteins
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt