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

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.

• Authors: Mitsuhiko Osaki, Satoru Kase, Keiko Adachi, Ami Takeda, Kiyoshi Hashimoto, Hisao Ito
• Journal: Journal of cancer research and clinical oncology (J Cancer Res Clin Oncol) Vol. 130 Issue 1 Pg. 8-14 (Jan 2004) ISSN: 0171-5216 [Print] Germany
• PMID: 14605879 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Carcinoma (drug therapy, 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, metabolism)