Abstract
The aim of this study was to ascertain whether LY294002, an inhibitor of PI-3K, enhances heat sensitivity in human cancer cells regardless of their p53 status. Colony formation assays showed that LY294002 enhanced heat sensitivity in two human lung cancer cell lines; H1299/wild-type p53 (wtp53) and H1299/mutated p53 (mp53) cells. These cell lines have identical genetic backgrounds except for their p53 status. LY294002 suppressed the heat-induced accumulation of heat shock protein 27 (hsp27) and heat shock protein 72 (hsp72) in these cell lines. Heat-induced apoptosis was observed more frequently in H1299/wtp53 cells than in H1299/mp53 cells, and was enhanced by LY294002 in both cell lines. In addition, both the heat-induced phosphorylation of Akt and the accumulation of survivin were suppressed by LY294002. These results suggest that LY294002 inhibits anti-apoptosis signaling through hsp27 and hsp72 as well as cell survival signaling through Akt and survivin. LY294002 appears to be an attractive candidate for a p53-independent heat sensitizer in hyperthermic cancer therapy.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Cell Line, Tumor
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Cell Survival / drug effects
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Chromones / pharmacology*
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DNA / metabolism
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DNA-Binding Proteins / metabolism
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HSP27 Heat-Shock Proteins
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HSP72 Heat-Shock Proteins / genetics
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HSP72 Heat-Shock Proteins / metabolism
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Heat Shock Transcription Factors
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Heat-Shock Proteins / metabolism
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Hot Temperature*
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Humans
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Hyperthermia, Induced*
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Inhibitor of Apoptosis Proteins
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Lung Neoplasms / enzymology*
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Lung Neoplasms / genetics
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Lung Neoplasms / therapy
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Microtubule-Associated Proteins / metabolism
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Molecular Chaperones
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Morpholines / pharmacology*
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Mutation
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Neoplasm Proteins / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins c-akt / metabolism
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Response Elements / genetics
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Survivin
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Transcription Factors / metabolism
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Transfection
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Tumor Stem Cell Assay
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Up-Regulation / drug effects
Substances
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BIRC5 protein, human
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Chromones
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DNA-Binding Proteins
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HSP27 Heat-Shock Proteins
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HSP72 Heat-Shock Proteins
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HSPB1 protein, human
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Heat Shock Transcription Factors
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Heat-Shock Proteins
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Inhibitor of Apoptosis Proteins
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Microtubule-Associated Proteins
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Molecular Chaperones
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Morpholines
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Neoplasm Proteins
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Survivin
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Transcription Factors
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Tumor Suppressor Protein p53
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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DNA
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Proto-Oncogene Proteins c-akt