RRC ID 1328
Author Osaki M, Kase S, Adachi K, Takeda A, Hashimoto K, Ito H.
Title Inhibition of the PI3K-Akt signaling pathway enhances the sensitivity of Fas-mediated apoptosis in human gastric carcinoma cell line, MKN-45.
Journal J. Cancer Res. Clin. Oncol.
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.
Volume 130(1)
Pages 8-14
Published 2004-1
DOI 10.1007/s00432-003-0505-z
PMID 14605879
MeSH 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* Phosphatidylinositol 3-Kinases / antagonists & 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
IF 3.332
Times Cited 64
Human and Animal Cells MKN45